WorldWideScience

Sample records for broad-spectrum proteinaceous antifungal

  1. Clinical evaluation of clotrimazole. A broad-spectrum antifungal agent.

    Science.gov (United States)

    Spiekermann, P H; Young, M D

    1976-03-01

    The efficacy and safety of the broad-spectrum, topically applied antifungal agent clotrimazole were evaluated in two double-blind, multicentric trials. Ten investigators reported on a total of 1,361 cases in which a 1% solution or a 1% cream formulation was compared with its respective vehicle. Clotrimazole was therapeutically effective, as confirmed by mycological cure (negative microscopy and culture) and clinical improvement, in tinea pedis, tinea cruris, tinea corporis, pityriasis versicolor, and cutaneous candidasis. Furthermore, species identification established the efficacy of clotrimazole against Trichophyton rubrum, T mentagrophytes, Epidermophyton floccosum, Microsporum canis, Malassezia furfur (Pityrosporum orbiculare), and Candida albicans. Safety was demonstrated by the low incidence of possibly drug-related adverse experiences, namely, 19 (2.7%) of 699 patients who were treated with clotrimazole, of whom four (0.6%) discontinued treatment.

  2. Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway

    Science.gov (United States)

    Thangamani, Shankar; Maland, Matthew; Mohammad, Haroon; Pascuzzi, Pete E.; Avramova, Larisa; Koehler, Carla M.; Hazbun, Tony R.; Seleem, Mohamed N.

    2017-01-01

    Current antifungal therapies have limited effectiveness in treating invasive fungal infections. Furthermore, the development of new antifungal is currently unable to keep pace with the urgent demand for safe and effective new drugs. Auranofin, an FDA-approved drug for the treatment of rheumatoid arthritis, inhibits growth of a diverse array of clinical isolates of fungi and represents a new antifungal agent with a previously unexploited mechanism of action. In addition to auranofin's potent antifungal activity against planktonic fungi, this drug significantly reduces the metabolic activity of Candida cells encased in a biofilm. Unbiased chemogenomic profiling, using heterozygous S. cerevisiae deletion strains, combined with growth assays revealed three probable targets for auranofin's antifungal activity—mia40, acn9, and coa4. Mia40 is of particular interest given its essential role in oxidation of cysteine rich proteins imported into the mitochondria. Biochemical analysis confirmed auranofin targets the Mia40-Erv1 pathway as the drug inhibited Mia40 from interacting with its substrate, Cmc1, in a dose-dependent manner similar to the control, MB-7. Furthermore, yeast mitochondria overexpressing Erv1 were shown to exhibit resistance to auranofin as an increase in Cmc1 import was observed compared to wild-type yeast. Further in vivo antifungal activity of auranofin was examined in a Caenorhabditis elegans animal model of Cryptococcus neoformans infection. Auranofin significantly reduced the fungal load in infected C. elegans. Collectively, the present study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antifungal agent and may offer a safe, effective, and quick supplement to current approaches for treating fungal infections. PMID:28149831

  3. Fungal Glucosylceramide-Specific Camelid Single Domain Antibodies Are Characterized by Broad Spectrum Antifungal Activity

    Directory of Open Access Journals (Sweden)

    Barbara De Coninck

    2017-06-01

    Full Text Available Chemical crop protection is widely used to control plant diseases. However, the adverse effects of pesticide use on human health and environment, resistance development and the impact of regulatory requirements on the crop protection market urges the agrochemical industry to explore innovative and alternative approaches. In that context, we demonstrate here the potential of camelid single domain antibodies (VHHs generated against fungal glucosylceramides (fGlcCer, important pathogenicity factors. To this end, llamas were immunized with purified fGlcCer and a mixture of mycelium and spores of the fungus Botrytis cinerea, one of the most important plant pathogenic fungi. The llama immune repertoire was subsequently cloned in a phage display vector to generate a library with a diversity of at least 108 different clones. This library was incubated with fGlcCer to identify phages that bind to fGlcCer, and VHHs that specifically bound fGlcCer but not mammalian or plant-derived GlcCer were selected. They were shown to inhibit the growth of B. cinerea in vitro, with VHH 41D01 having the highest antifungal activity. Moreover, VHH 41D01 could reduce disease symptoms induced by B. cinerea when sprayed on tomato leaves. Based on all these data, anti-fGlcCer VHHs show the potential to be used as an alternative approach to combat fungal plant diseases.

  4. A novel antifungal agent with broad spectrum: 1-(4-biphenylyl)-3-(1H-imidazol-1-yl)-1-propanone.

    Science.gov (United States)

    Roman, Gheorghe; Mareş, Mihai; Năstasă, Valentin

    2013-02-01

    A series of (1-substituted aryl)-3-(1H-imidazol-1-yl)-1-propanones was synthesized through the N-alkylation of imidazole with 3-dimethylamino-1-(substituted aryl)-1-propanone hydrochlorides (ketonic Mannich bases). A second series of N(1) -substituted imidazoles was obtained by the reduction of the carbonyl function of the imidazole-ketones in the previous series by means of NaBH(4) . All of the compounds were evaluated for antifungal activity against 16 strains of Candida, and 3-(1H-imidazol-1-yl)-1-(4-biphenylyl)-1-propanone emerged as a broad-spectrum antifungal agent. Several 3-(1H-imidazol-1-yl)-1-(2'-(substituted benzyl)oxyphenyl)-1-propanones were also active towards Candida kefyr. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. In vitro activity of a novel broad-spectrum antifungal, E1210, tested against Aspergillus spp. determined by CLSI and EUCAST broth microdilution methods.

    Science.gov (United States)

    Pfaller, Michael A; Duncanson, Frederick; Messer, Shawn A; Moet, Gary J; Jones, Ronald N; Castanheira, Mariana

    2011-11-01

    E1210 is a first-in-class broad-spectrum antifungal that suppresses hyphal growth by inhibiting fungal glycophosphatidylinositol (GPI) biosynthesis. In the present study, we extend these findings by examining the activity of E1210 and comparator antifungal agents against Aspergillus spp. by using the methods of the Clinical and Laboratory Standards Institute (CLSI) and the European Committee for Antimicrobial Susceptibility Testing (EUCAST) to test wild-type (WT) as well as amphotericin B (AMB)-resistant (-R) and azole-R strains (as determined by CLSI methods). Seventy-eight clinical isolates of Aspergillus were tested including 20 isolates of Aspergillus flavus species complex (SC), 22 of A. fumigatus SC, 13 of A. niger SC, and 23 of A. terreus SC. The collection included 15 AMB-R (MIC, ≥ 2 μg/ml) isolates of A. terreus SC and 10 itraconazole-R (MIC, ≥ 4 μg/ml) isolates of A. fumigatus SC (7 isolates), A. niger SC (2 isolates), and A. terreus SC (1 isolate). Comparator antifungal agents included anidulafungin, caspofungin, amphotericin B, itraconazole, posaconzole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparators. The essential agreement (EA; ± 2 log(2) dilution steps) was 100% for all comparisons with the exception of posaconazole versus A. terreus SC (EA = 91.3%). The minimum effective concentration (MEC)/MIC(90) values (μg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, and voriconazole, respectively, were as follows for each species: for A. flavus SC, 0.03, ≤ 0.008, 0.12, 1, 1, and 1; for A. fumigatus SC, 0.06, 0.015, 0.12, >8, 1, and 4; for A. niger SC, 0.015, 0.03, 0.12, 4, 1, and 2; and for A. terreus SC, 0.06, 0.015, 0.12, 1, 0.5, and 1. E1210 was very active against AMB-R strains of A. terreus SC (MEC range, 0.015 to 0.06 μg/ml) and itraconazole-R strains of A. fumigatus SC (MEC range, 0.03 to 0.12 μg/ml), A. niger SC (MEC, 0.008 μg/ml), and A. terreus SC (MEC, 0.015

  6. In Vitro Activity of a Novel Broad-Spectrum Antifungal, E1210, Tested against Aspergillus spp. Determined by CLSI and EUCAST Broth Microdilution Methods ▿

    Science.gov (United States)

    Pfaller, Michael A.; Duncanson, Frederick; Messer, Shawn A.; Moet, Gary J.; Jones, Ronald N.; Castanheira, Mariana

    2011-01-01

    E1210 is a first-in-class broad-spectrum antifungal that suppresses hyphal growth by inhibiting fungal glycophosphatidylinositol (GPI) biosynthesis. In the present study, we extend these findings by examining the activity of E1210 and comparator antifungal agents against Aspergillus spp. by using the methods of the Clinical and Laboratory Standards Institute (CLSI) and the European Committee for Antimicrobial Susceptibility Testing (EUCAST) to test wild-type (WT) as well as amphotericin B (AMB)-resistant (-R) and azole-R strains (as determined by CLSI methods). Seventy-eight clinical isolates of Aspergillus were tested including 20 isolates of Aspergillus flavus species complex (SC), 22 of A. fumigatus SC, 13 of A. niger SC, and 23 of A. terreus SC. The collection included 15 AMB-R (MIC, ≥2 μg/ml) isolates of A. terreus SC and 10 itraconazole-R (MIC, ≥4 μg/ml) isolates of A. fumigatus SC (7 isolates), A. niger SC (2 isolates), and A. terreus SC (1 isolate). Comparator antifungal agents included anidulafungin, caspofungin, amphotericin B, itraconazole, posaconzole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparators. The essential agreement (EA; ±2 log2 dilution steps) was 100% for all comparisons with the exception of posaconazole versus A. terreus SC (EA = 91.3%). The minimum effective concentration (MEC)/MIC90 values (μg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, and voriconazole, respectively, were as follows for each species: for A. flavus SC, 0.03, ≤0.008, 0.12, 1, 1, and 1; for A. fumigatus SC, 0.06, 0.015, 0.12, >8, 1, and 4; for A. niger SC, 0.015, 0.03, 0.12, 4, 1, and 2; and for A. terreus SC, 0.06, 0.015, 0.12, 1, 0.5, and 1. E1210 was very active against AMB-R strains of A. terreus SC (MEC range, 0.015 to 0.06 μg/ml) and itraconazole-R strains of A. fumigatus SC (MEC range, 0.03 to 0.12 μg/ml), A. niger SC (MEC, 0.008 μg/ml), and A. terreus SC (MEC, 0.015

  7. Efficacy of oral E1210, a new broad-spectrum antifungal with a novel mechanism of action, in murine models of candidiasis, aspergillosis, and fusariosis.

    Science.gov (United States)

    Hata, Katsura; Horii, Takaaki; Miyazaki, Mamiko; Watanabe, Nao-Aki; Okubo, Miyuki; Sonoda, Jiro; Nakamoto, Kazutaka; Tanaka, Keigo; Shirotori, Syuji; Murai, Norio; Inoue, Satoshi; Matsukura, Masayuki; Abe, Shinya; Yoshimatsu, Kentaro; Asada, Makoto

    2011-10-01

    E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action-inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. Oral E1210 demonstrated dose-dependent efficacy in infections caused by Candida species, Aspergillus spp., and Fusarium solani. In the treatment of oropharyngeal candidiasis, E1210 and fluconazole each caused a significantly greater reduction in the number of oral CFU than the control treatment (P candidiasis model, mice treated with E1210, fluconazole, caspofungin, or liposomal amphotericin B showed significantly higher survival rates than the control mice (P candidiasis caused by azole-resistant Candida albicans or Candida tropicalis. A 24-h delay in treatment onset minimally affected the efficacy outcome of E1210 in the treatment of disseminated candidiasis. In the Aspergillus flavus pulmonary aspergillosis model, mice treated with E1210, voriconazole, or caspofungin showed significantly higher survival rates than the control mice (P candidiasis, pulmonary aspergillosis, and disseminated fusariosis. These data suggest that further studies to determine E1210's potential for the treatment of disseminated fungal infections are indicated.

  8. Fungal Root Microbiome from Healthy and Brittle Leaf Diseased Date Palm Trees (Phoenix dactylifera L.) Reveals a Hidden Untapped Arsenal of Antibacterial and Broad Spectrum Antifungal Secondary Metabolites.

    Science.gov (United States)

    Mefteh, Fedia B; Daoud, Amal; Chenari Bouket, Ali; Alenezi, Faizah N; Luptakova, Lenka; Rateb, Mostafa E; Kadri, Adel; Gharsallah, Neji; Belbahri, Lassaad

    2017-01-01

    In this study, we aimed to explore and compare the composition, metabolic diversity and antimicrobial potential of endophytic fungi colonizing internal tissues of healthy and brittle leaf diseased (BLD) date palm trees (Phoenix dactylifera L.) widely cultivated in arid zones of Tunisia. A total of 52 endophytic fungi were isolated from healthy and BLD roots of date palm trees, identified based on internal transcribed spacer-rDNA sequence analysis and shown to represent 13 species belonging to five genera. About 36.8% of isolates were shared between healthy and diseased root fungal microbiomes, whereas 18.4 and 44.7% of isolates were specific to healthy and BLD root fungal microbiomes, respectively. All isolates were able to produce at least two of the screened enzymes including amylase, cellulase, chitinase, pectinase, protease, laccase and lipase. A preliminary screening of the isolates using disk diffusion method for antibacterial activity against four Gram-positive and three Gram-negative bacteria and antifungal activities against three phytopathogenic fungi indicated that healthy and BLD root fungal microbiomes displayed interesting bioactivities against examined bacteria and broad spectrum bioactivity against fungal pathogens. Some of these endophytic fungi (17 isolates) were fermented and their extracts were evaluated for antimicrobial potential against bacterial and fungal isolates. Results revealed that fungal extracts exhibited antibacterial activities and were responsible for approximately half of antifungal activities against living fungi. These results suggest a strong link between fungal bioactivities and their secondary metabolite arsenal. EtOAc extracts of Geotrichum candidum and Thielaviopsis punctulata originating from BLD microbiome gave best results against Micrococcus luteus and Bacillus subtilis with minimum inhibitory concentration (MIC, 0.78 mg/mL) and minimum bactericidal concentration (6.25 mg/mL). G. candidum gave the best result against

  9. Fungal Root Microbiome from Healthy and Brittle Leaf Diseased Date Palm Trees (Phoenix dactylifera L.) Reveals a Hidden Untapped Arsenal of Antibacterial and Broad Spectrum Antifungal Secondary Metabolites

    Science.gov (United States)

    Mefteh, Fedia B.; Daoud, Amal; Chenari Bouket, Ali; Alenezi, Faizah N.; Luptakova, Lenka; Rateb, Mostafa E.; Kadri, Adel; Gharsallah, Neji; Belbahri, Lassaad

    2017-01-01

    In this study, we aimed to explore and compare the composition, metabolic diversity and antimicrobial potential of endophytic fungi colonizing internal tissues of healthy and brittle leaf diseased (BLD) date palm trees (Phoenix dactylifera L.) widely cultivated in arid zones of Tunisia. A total of 52 endophytic fungi were isolated from healthy and BLD roots of date palm trees, identified based on internal transcribed spacer-rDNA sequence analysis and shown to represent 13 species belonging to five genera. About 36.8% of isolates were shared between healthy and diseased root fungal microbiomes, whereas 18.4 and 44.7% of isolates were specific to healthy and BLD root fungal microbiomes, respectively. All isolates were able to produce at least two of the screened enzymes including amylase, cellulase, chitinase, pectinase, protease, laccase and lipase. A preliminary screening of the isolates using disk diffusion method for antibacterial activity against four Gram-positive and three Gram-negative bacteria and antifungal activities against three phytopathogenic fungi indicated that healthy and BLD root fungal microbiomes displayed interesting bioactivities against examined bacteria and broad spectrum bioactivity against fungal pathogens. Some of these endophytic fungi (17 isolates) were fermented and their extracts were evaluated for antimicrobial potential against bacterial and fungal isolates. Results revealed that fungal extracts exhibited antibacterial activities and were responsible for approximately half of antifungal activities against living fungi. These results suggest a strong link between fungal bioactivities and their secondary metabolite arsenal. EtOAc extracts of Geotrichum candidum and Thielaviopsis punctulata originating from BLD microbiome gave best results against Micrococcus luteus and Bacillus subtilis with minimum inhibitory concentration (MIC, 0.78 mg/mL) and minimum bactericidal concentration (6.25 mg/mL). G. candidum gave the best result against

  10. Broad-spectrum antiviral agents

    Directory of Open Access Journals (Sweden)

    Jun-Da eZhu

    2015-05-01

    Full Text Available Development of highly effective, broad-spectrum antiviral agents is the major objective shared by the fields of virology and pharmaceutics. Antiviral drug development has focused on targeting viral entry and replication, as well as modulating cellular defense system. High throughput screening of molecules, genetic engineering of peptides, and functional screening of agents have identified promising candidates for development of optimal broad-spectrum antiviral agents to intervene in viral infection and control viral epidemics. This review discusses current knowledge, prospective applications, opportunities, and challenges in the development of broad-spectrum antiviral agents.

  11. Broad-spectrum antiviral therapeutics.

    Directory of Open Access Journals (Sweden)

    Todd H Rider

    Full Text Available Currently there are relatively few antiviral therapeutics, and most which do exist are highly pathogen-specific or have other disadvantages. We have developed a new broad-spectrum antiviral approach, dubbed Double-stranded RNA (dsRNA Activated Caspase Oligomerizer (DRACO that selectively induces apoptosis in cells containing viral dsRNA, rapidly killing infected cells without harming uninfected cells. We have created DRACOs and shown that they are nontoxic in 11 mammalian cell types and effective against 15 different viruses, including dengue flavivirus, Amapari and Tacaribe arenaviruses, Guama bunyavirus, and H1N1 influenza. We have also demonstrated that DRACOs can rescue mice challenged with H1N1 influenza. DRACOs have the potential to be effective therapeutics or prophylactics for numerous clinical and priority viruses, due to the broad-spectrum sensitivity of the dsRNA detection domain, the potent activity of the apoptosis induction domain, and the novel direct linkage between the two which viruses have never encountered.

  12. Broad spectrum antibiotic compounds and use thereof

    Energy Technology Data Exchange (ETDEWEB)

    Koglin, Alexander; Strieker, Matthias

    2016-07-05

    The discovery of a non-ribosomal peptide synthetase (NRPS) gene cluster in the genome of Clostridium thermocellum that produces a secondary metabolite that is assembled outside of the host membrane is described. Also described is the identification of homologous NRPS gene clusters from several additional microorganisms. The secondary metabolites produced by the NRPS gene clusters exhibit broad spectrum antibiotic activity. Thus, antibiotic compounds produced by the NRPS gene clusters, and analogs thereof, their use for inhibiting bacterial growth, and methods of making the antibiotic compounds are described.

  13. Isavuconazole: A New Broad-Spectrum Triazole Antifungal Agent.

    Science.gov (United States)

    Miceli, Marisa H; Kauffman, Carol A

    2015-11-15

    Isavuconazole is a new extended-spectrum triazole with activity against yeasts, molds, and dimorphic fungi. It is approved for the treatment of invasive aspergillosis and mucormycosis. Advantages of this triazole include the availability of a water-soluble intravenous formulation, excellent bioavailability of the oral formulation, and predictable pharmacokinetics in adults. A randomized, double-blind comparison clinical trial for treatment of invasive aspergillosis found that the efficacy of isavuconazole was noninferior to that of voriconazole. An open-label trial that studied primary as well as salvage therapy of invasive mucormycosis showed efficacy with isavuconazole that was similar to that reported for amphotericin B and posaconazole. In patients in these studies, as well as in normal volunteers, isavuconazole was well tolerated, appeared to have few serious adverse effects, and had fewer drug-drug interactions than those noted with voriconazole. As clinical experience increases, the role of this new triazole in the treatment of invasive fungal infections will be better defined.

  14. Broad spectrum anthelmintic potential of Cassia plants

    Institute of Scientific and Technical Information of China (English)

    Suman Kundu; Saptarshi Roy; Larisha Mawkhleing Lyndem

    2014-01-01

    Objective: To study the in vitro anthelmintic efficacy of Cassia alata (C. alata), Cassia(C. angustifolia) and Cassia occidentalis (C. occidentalis). angustifolia Methods: Crude ethanol extract from leaves of the three plants were prepared in rotary evaporator and different concentrations (10, 20 and 40 mg/mL) of leaf extracts were used for treatment on different representatives of helminthes (Heterakis gallinarum, Raillietina tetragona and Catatropis sp.) from domestic fowl (Gallus gallus domesticus). Loss of motility and death were monitored frequently.Results: C. alata showed early paralysis in all worms treated followed by C. angustifolia. C. occidentalis in combination with C. alata together caused early paralysis in all treated worms than the combination of C. alata with C. angustfolia. While Heterakis gallinarum in control survived for (81.33±2.07) h, treated worms lost their motility at (5.71±0.10) h, (6.60±0.86) h and (13.95±0.43) h with C. angustifolia, C. alata and C. occidentalis respectively at a concentration of 40 mg/mL which showed better efficacy than albendazole. Catatropis sp. survival period was (26.49±1.38) h in control, but with plant treatment, it lost its motility in just (0.57±0.08) h, (1.00±0.12) h and (1.47±0.40) h at 40 mg/mL concentration of C. alata, C. angustifolia and C. occidentalis respectively.Raillietina tetragona on the other hand became paralysed at (1.68±0.27) h, (2.95±0.29) h and (4.13±0.31) h with above concentrations treated with three plants respectively, however in control it survived up to (81.93±4.71) h.Conclusions:This present study indicated broad spectrum vermifugal activity of all plants tested.

  15. Functional assignment of YvgO, a novel set of purified and chemically characterized proteinaceous antifungal variants produced by Bacillus thuringiensis SF361.

    Science.gov (United States)

    Manns, David C; Churey, John J; Worobo, Randy W

    2012-04-01

    This study reports a novel class of antifungal protein derived from bacterial origin. Bacillus thuringiensis SF361, the strain also responsible for producing the novel bacteriocin thurincin H, exhibits broad antifungal activity against select members of several fungal genera, including Aspergillus, Byssochlamys, and Penicillium, as well as the pathogenic yeast Candida albicans. Optimal antifungal production and secretion were observed after-log phase growth when incubated at 37°C in a carbohydrate-free growth medium. High-performance liquid chromatography purification was performed after pH-selective ammonium sulfate precipitation and size-exclusion chromatography. Intact mass analysis and peptide mass fingerprinting identified the 13,484-Da protein to be a mass homolog to the YvgO protein construct sequenced from Bacillus cereus AH 1134. Further analysis via amino-terminal sequencing also revealed the existence of four distinct yet equally efficacious YvgO variants differing only within the first four N-terminal residues. YvgO was found to be remarkably stable, maintaining its antifungal activity under a wide pH and temperature range. When assayed against the toxigenic species Byssochlamys fulva H25, the selected primary filamentous fungal indicator, the MIC was estimated to be 1.5 ppm. Candida albicans 3153 was more resistant, exhibiting MICs between 25 and 800 ppm, depending on growth conditions. YvgO is unique among antifungals, showing no known sequential or functional homology to the typical classes of antifungal proteins, including common membrane-acting agents such as cellulases and glucanases. Due to its activity against an array of pathogenic and spoilage fungi, the potentials for clinical, agricultural, and food-processing applications are encouraging.

  16. On the Operational Meaning of Broad-Spectrum Philosophy Methodology

    Directory of Open Access Journals (Sweden)

    Miao Yi

    2012-06-01

    Full Text Available This study analyze the Broad-spectrum Philosophy Methodology on the operational meaning, and discusses three relatively primary methods of Broad-spectrum Philosophy Methodologies. The methodology of Broad-spectrum philosophy cannot pursuit of accuracy of numerical sense, but it pursuits of the exact nature of the research questions, the accuracy of the sense of set theory and sums up the experience which we solve problems in real life and make it up to the generalized quantization and procedural level and thus the methodology of Broad-spectrum philosophy has a general guide and it is a broad operations research. We gets the results that along with deep exploration and development of Broad-spectrum Philosophy Methodology, its function as generalized operation research can be more powerful.

  17. Broad Spectrum Sanitizing Wipes with Food Additives Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Microcide proposes to develop novel multipurpose non-toxic sanitizing wipes that are aqueous based, have shelf life of 3-5 years, have broad spectrum microbicidal...

  18. Variable Efficacy of the Proteinaceous Antifungal YvgO in Select Fruit Juices and Teas as a Complement with UV Methods of Food Protection.

    Science.gov (United States)

    Manns, David C; Churey, John J; Worobo, Randy W

    2015-10-01

    Heat-resistant fungal spores present a processing challenge for beverages and fruit juices, as thermal and UV strategies are often inadequate in reducing heat-resistant fungal burdens to acceptable levels. While effective against pathogenic or invasive bacteria, germicidal UV light treatments also fail to achieve an appreciable reduction of heat-resistant fungal spores. As an alternative, the efficacy of the antifungal protein YvgO was examined across a selection of fruit juices and teas, as well as solid model matrices. Compared with its efficacy in analogous liquid matrices, the apparent efficacy of YvgO was diminished on acidified solid matrices due to a reduction in YvgO diffusion. Using an XTT [2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] tetrazolium dye cytotoxicity assay, the effective concentrations to reduce growth by 50% were elucidated in samples challenged with Byssochlamys fulva H25. The MICs were determined and ranged from 2 ppm in apple juice and acidified teas to approximately 3 to 12 ppm for lemonade and orange, white cranberry, blueberry, prune, cherry, and grape juices. Apple cider and nonacidified teas showed reduced efficacy, with MICs exceeding 100 ppm. Tannin-rich products readily removed YvgO from the product, impairing its efficacy. Adding bovine serum albumin as a competitive inhibitor effectively reversed the YvgO-tannin association and restored efficacy in black but not green tea matrices. When challenged with a 5-log CFU inoculum of B. fulva, the shelf lives of the products were extended for various times up to 28 days in a concentrationdependent manner. However, initial efficacy was not predictive of shelf life extension, as some products exhibited improved protection at just two- and fourfold concentrations above the MIC, while others only exhibited long-term stability when concentrations exceeded 20 times the MIC. As such, YvgO may be an attractive alternative to currently available protection strategies

  19. Broad spectrum antiangiogenic treatment for ocular neovascular diseases.

    Directory of Open Access Journals (Sweden)

    Ofra Benny

    Full Text Available UNLABELLED: Pathological neovascularization is a hallmark of late stage neovascular (wet age-related macular degeneration (AMD and the leading cause of blindness in people over the age of 50 in the western world. The treatments focus on suppression of choroidal neovascularization (CNV, while current approved therapies are limited to inhibiting vascular endothelial growth factor (VEGF exclusively. However, this treatment does not address the underlying cause of AMD, and the loss of VEGF's neuroprotective can be a potential side effect. Therapy which targets the key processes in AMD, the pathological neovascularization, vessel leakage and inflammation could bring a major shift in the approach to disease treatment and prevention. In this study we have demonstrated the efficacy of such broad spectrum antiangiogenic therapy on mouse model of AMD. METHODS AND FINDINGS: Lodamin, a polymeric formulation of TNP-470, is a potent broad-spectrum antiangiogenic drug. Lodamin significantly reduced key processes involved in AMD progression as demonstrated in mice and rats. Its suppressive effects on angiogenesis, vascular leakage and inflammation were studied in a wide array of assays including; a Matrigel, delayed-type hypersensitivity (DTH, Miles assay, laser-induced CNV and corneal micropocket assay. Lodamin significantly suppressed the secretion of various pro-inflammatory cytokines in the CNV lesion including monocyte chemotactic protein-1 (MCP-1/Ccl2. Importantly, Lodamin was found to regress established CNV lesions, unlike soluble fms-like tyrosine kinase-1 (sFlk-1. The drug was found to be safe in mice and have little toxicity as demonstrated by electroretinography (ERG assessing retinal and by histology. CONCLUSIONS: Lodamin, a polymer formulation of TNP-470, was identified as a first in its class, broad-spectrum antiangiogenic drug that can be administered orally or locally to treat corneal and retinal neovascularization. Several unique properties

  20. The broad spectrum revisited: Evidence from plant remains

    OpenAIRE

    Weiss, Ehud; Wetterstrom, Wilma; Nadel, Dani; Bar-Yosef, Ofer

    2004-01-01

    The beginning of agriculture is one of the most important developments in human history, with enormous consequences that paved the way for settled life and complex society. Much of the research on the origins of agriculture over the last 40 years has been guided by Flannery's [Flannery, K. V. (1969) in The Domestication and Exploitation of Plants and Animals, eds. Ucko, P. J. & Dimbleby, G. W. (Duckworth, London), pp. 73–100] “broad spectrum revolution” (BSR) hypothesis, which posits that the...

  1. Brevibacillus laterosporus, a Pathogen of Invertebrates and a Broad-Spectrum Antimicrobial Species

    Directory of Open Access Journals (Sweden)

    Luca Ruiu

    2013-09-01

    Full Text Available Brevibacillus laterosporus, a bacterium characterized by the production of a unique canoe-shaped lamellar body attached to one side of the spore, is a natural inhabitant of water, soil and insects. Its biopesticidal potential has been reported against insects in different orders including Coleoptera, Lepidoptera, Diptera and against nematodes and mollusks. In addition to its pathogenicity against invertebrates, different B. laterosporus strains show a broad-spectrum antimicrobial activity including activity against phytopathogenic bacteria and fungi. A wide variety of molecules, including proteins and antibiotics, have been associated with the observed pathogenicity and mode of action. Before being considered as a biological control agent against plant pathogens, the antifungal and antibacterial properties of certain B. laterosporus strains have found medical interest, associated with the production of antibiotics with therapeutic effects. The recent whole genome sequencing of this species revealed its potential to produce polyketides, nonribosomal peptides, and toxins. Another field of growing interest is the use of this bacterium for bioremediation of contaminated sites by exploiting its biodegradation properties. The aim of the present review is to gather and discuss all recent findings on this emerging entomopathogen, giving a wider picture of its complex and broad-spectrum biocontrol activity.

  2. Brevibacillus laterosporus, a Pathogen of Invertebrates and a Broad-Spectrum Antimicrobial Species.

    Science.gov (United States)

    Ruiu, Luca

    2013-09-05

    Brevibacillus laterosporus, a bacterium characterized by the production of a unique canoe-shaped lamellar body attached to one side of the spore, is a natural inhabitant of water, soil and insects. Its biopesticidal potential has been reported against insects in different orders including Coleoptera, Lepidoptera, Diptera and against nematodes and mollusks. In addition to its pathogenicity against invertebrates, different B. laterosporus strains show a broad-spectrum antimicrobial activity including activity against phytopathogenic bacteria and fungi. A wide variety of molecules, including proteins and antibiotics, have been associated with the observed pathogenicity and mode of action. Before being considered as a biological control agent against plant pathogens, the antifungal and antibacterial properties of certain B. laterosporus strains have found medical interest, associated with the production of antibiotics with therapeutic effects. The recent whole genome sequencing of this species revealed its potential to produce polyketides, nonribosomal peptides, and toxins. Another field of growing interest is the use of this bacterium for bioremediation of contaminated sites by exploiting its biodegradation properties. The aim of the present review is to gather and discuss all recent findings on this emerging entomopathogen, giving a wider picture of its complex and broad-spectrum biocontrol activity.

  3. Isolation and Characterization of a Broad Spectrum Bacteriocin from Bacillus amyloliquefaciens RX7.

    Science.gov (United States)

    Lim, Kong Boon; Balolong, Marilen P; Kim, Sang Hoon; Oh, Ju Kyoung; Lee, Ji Yoon; Kang, Dae-Kyung

    2016-01-01

    We isolated a Bacillus strain, RX7, with inhibitory activity against Listeria monocytogenes from soil and identified it as Bacillus amyloliquefaciens based on 16S rRNA gene sequencing. The inhibitory activity was stable over a wide range of pH and was fully retained after 30 min at 80°C, after which it decreased gradually at higher temperatures. The activity was sensitive to the proteolytic action of α-chymotrypsin, proteinase-K, and trypsin, indicating its proteinaceous nature. This bacteriocin was active against a broad spectrum of bacteria and the fungus Candida albicans. Direct detection of antimicrobial activity on a sodium dodecyl sulfate-polyacrylamide gel suggested an apparent molecular mass of approximately 5 kDa. Ammonium sulfate precipitation and anion-exchange and gel permeation chromatography integrated with reverse phase-high-performance liquid chromatography were used for bacteriocin purification. Automated N-terminal Edman degradation of the purified RX7 bacteriocin recognized the first 15 amino acids as NH2-X-Ala-Trp-Tyr-Asp-Ile-Arg-Lys-Leu-Gly-Asn-Lys-Gly-Ala, where the letter X in the sequence indicates an unknown or nonstandard amino acid. Based on BLAST similarity search and multiple alignment analysis, the obtained partial sequence showed high homology with the two-peptide lantibiotic haloduracin (HalA1) from Bacillus halodurans, although at least two amino acids differed between the sequences. A time-kill study demonstrated a bactericidal mode of action of RX7 bacteriocin.

  4. Multivalent dendritic molecules as broad spectrum bacteria agglutination agents.

    Science.gov (United States)

    Xiao, Shuzhang; Abu-Esba, Lica; Turkyilmaz, Serhan; White, Alexander G; Smith, Bradley D

    2013-01-01

    This study reports the first set of synthetic molecules that act as broad spectrum agglutination agents and thus are complementary to the specific targeting of antibodies. The molecules have dendritic architecture and contain multiple copies of zinc(II)-dipicolylamine (ZnDPA) units that have selective affinity for the bacterial cell envelope. A series of molecular structures were evaluated, with the number of appended ZnDPA units ranging from four to thirty-two. Agglutination assays showed that the multivalent probes rapidly cross-linked ten different strains of bacteria, regardless of Gram-type and cell morphology. Fluorescence microscopy studies using probes with four ZnDPA units indicated a high selectivity for bacteria agglutination in the presence of mammalian cells and no measurable effect on the health of the cells. The high bacterial selectivity was confirmed by conducting in vivo optical imaging studies of a mouse leg infection model. The results suggest that multivalent ZnDPA molecular probes with dendritic structures have great promise as selective, broad spectrum bacterial agglutination agents for infection imaging and theranostic applications.

  5. Broad-spectrum antimicrobial polycarbonate hydrogels with fast degradability.

    Science.gov (United States)

    Pascual, Ana; Tan, Jeremy P K; Yuen, Alex; Chan, Julian M W; Coady, Daniel J; Mecerreyes, David; Hedrick, James L; Yang, Yi Yan; Sardon, Haritz

    2015-04-13

    In this study, a new family of broad-spectrum antimicrobial polycarbonate hydrogels has been successfully synthesized and characterized. Tertiary amine-containing eight-membered monofunctional and difunctional cyclic carbonates were synthesized, and chemically cross-linked polycarbonate hydrogels were obtained by copolymerizing these monomers with a poly(ethylene glycol)-based bifunctional initiator via organocatalyzed ring-opening polymerization using 1,8-diazabicyclo[5.4.0]undec-7-ene catalyst. The gels were quaternized using methyl iodide to confer antimicrobial properties. Stable hydrogels were obtained only when the bifunctional monomer concentration was equal to or higher than 12 mol %. In vitro antimicrobial studies revealed that all quaternized hydrogels exhibited broad-spectrum antimicrobial activity against Staphylococcus aureus (Gram-positive), Escherichia coli (Gram-negative), Pseudomonas aeruginosa (Gram-negative), and Candida albicans (fungus), while the antimicrobial activity of the nonquaternized hydrogels was negligible. Moreover, the gels showed fast degradation at room temperature (4-6 days), which makes them ideal candidates for wound healing and implantable biomaterials.

  6. Rufinamide: a novel broad-spectrum antiepileptic drug.

    Science.gov (United States)

    Wheless, James W; Vazquez, Blanca

    2010-01-01

    The last 20 years have witnessed a tremendous explosion in the number of antiepileptic drugs (AEDs) as well as the introduction of AEDS developed for specific epilepsy syndromes. The study of the efficacy and side effect profile of AEDs for unique epilepsy syndromes has allowed neurologists to utilize evidence-based medicine when treating patients. In late 2008, the Food and Drug Administration approved rufinamide for adjunctive use in the treatment of seizures associated with Lennox-Gastaut syndrome. This unique chemical compound is also the first new AED to reach the market in the United States having a pediatric indication prior to approval for adults. Rufinamide appears to have a broad spectrum of efficacy, is well tolerated, and may be rapidly initiated--properties that will likely extend its use outside of Lennox-Gastaut syndrome.

  7. Broad spectrum moderators and advanced reflector filters using 208Pb

    DEFF Research Database (Denmark)

    Schönfeldt, Troels; Batkov, K.; Klinkby, Esben Bryndt

    2015-01-01

    thermalizing property of 208Pb to design a broad spectrum moderator, i.e. a moderator which emits thermal and cold neutrons from the same position. Using 208Pb as a reflector filter material is shown to be slightly less efficient than a conventional beryllium reflector filter. However, when surrounding...... the reflector filter by a cold moderator it is possible to regain the neutrons with wavelengths below the Bragg edge, which are suppressed in the beryllium reflector filter. In both the beryllium and lead case surrounding the reflector filter with a cold moderator increases the cold brightness significantly......Cold and thermal neutrons used in neutrons scattering experiments are produced in nuclear reactors and spallation sources. The neutrons are cooled to thermal or cold temperatures in thermal and cold moderators, respectively. The present study shows that it is possible to exploit the poor...

  8. Isolation and Characterization of a Broad Spectrum Bacteriocin from Bacillus amyloliquefaciens RX7

    Directory of Open Access Journals (Sweden)

    Kong Boon Lim

    2016-01-01

    Full Text Available We isolated a Bacillus strain, RX7, with inhibitory activity against Listeria monocytogenes from soil and identified it as Bacillus amyloliquefaciens based on 16S rRNA gene sequencing. The inhibitory activity was stable over a wide range of pH and was fully retained after 30 min at 80°C, after which it decreased gradually at higher temperatures. The activity was sensitive to the proteolytic action of α-chymotrypsin, proteinase-K, and trypsin, indicating its proteinaceous nature. This bacteriocin was active against a broad spectrum of bacteria and the fungus Candida albicans. Direct detection of antimicrobial activity on a sodium dodecyl sulfate-polyacrylamide gel suggested an apparent molecular mass of approximately 5 kDa. Ammonium sulfate precipitation and anion-exchange and gel permeation chromatography integrated with reverse phase-high-performance liquid chromatography were used for bacteriocin purification. Automated N-terminal Edman degradation of the purified RX7 bacteriocin recognized the first 15 amino acids as NH2-X-Ala-Trp-Tyr-Asp-Ile-Arg-Lys-Leu-Gly-Asn-Lys-Gly-Ala, where the letter X in the sequence indicates an unknown or nonstandard amino acid. Based on BLAST similarity search and multiple alignment analysis, the obtained partial sequence showed high homology with the two-peptide lantibiotic haloduracin (HalA1 from Bacillus halodurans, although at least two amino acids differed between the sequences. A time-kill study demonstrated a bactericidal mode of action of RX7 bacteriocin.

  9. Broad spectrum microarray for fingerprint-based bacterial species identification

    Directory of Open Access Journals (Sweden)

    Frey Jürg E

    2010-02-01

    Full Text Available Abstract Background Microarrays are powerful tools for DNA-based molecular diagnostics and identification of pathogens. Most target a limited range of organisms and are based on only one or a very few genes for specific identification. Such microarrays are limited to organisms for which specific probes are available, and often have difficulty discriminating closely related taxa. We have developed an alternative broad-spectrum microarray that employs hybridisation fingerprints generated by high-density anonymous markers distributed over the entire genome for identification based on comparison to a reference database. Results A high-density microarray carrying 95,000 unique 13-mer probes was designed. Optimized methods were developed to deliver reproducible hybridisation patterns that enabled confident discrimination of bacteria at the species, subspecies, and strain levels. High correlation coefficients were achieved between replicates. A sub-selection of 12,071 probes, determined by ANOVA and class prediction analysis, enabled the discrimination of all samples in our panel. Mismatch probe hybridisation was observed but was found to have no effect on the discriminatory capacity of our system. Conclusions These results indicate the potential of our genome chip for reliable identification of a wide range of bacterial taxa at the subspecies level without laborious prior sequencing and probe design. With its high resolution capacity, our proof-of-principle chip demonstrates great potential as a tool for molecular diagnostics of broad taxonomic groups.

  10. 5-Alkyloxytryptamines are membrane-targeting, broad-spectrum antibiotics.

    Science.gov (United States)

    Faulkner, Katherine C; Hurley, Katherine A; Weibel, Douglas B

    2016-11-15

    Antibiotic adjuvant therapy represents an exciting opportunity to enhance the activity of clinical antibiotics by co-dosing with a secondary small molecule. Successful adjuvants decrease the concentration of antibiotics used to defeat bacteria, increase activity (in some cases introducing activity against organisms that are drug resistant), and reduce the frequency at which drug-resistant bacteria emerge. We report that 5-alkyloxytryptamines are a new class of broad-spectrum antibacterial agents with exciting activity as antibiotic adjuvants. We synthesized 5-alkyloxytryptamine analogs and found that an alkyl chain length of 6-12 carbons and a primary ammonium group are necessary for the antibacterial activity of the compounds, and an alkyl chain length of 6-10 carbons increased the membrane permeability of Gram-positive and Gram-negative bacteria. Although several of the most potent analogs also have activity against the membranes of human embryonic kidney cells, we demonstrate that below the minimum inhibitory concentration (MIC)-where mammalian cell toxicity is low-these compounds may be successfully used as adjuvants for chloramphenicol, tetracycline, ciprofloxacin, and rifampicin against clinical strains of Salmonella typhimurium, Acinetobacter baumannii and Staphylococcus aureus, reducing MIC values by as much as several logs.

  11. The broad spectrum revisited: Evidence from plant remains

    Science.gov (United States)

    Weiss, Ehud; Wetterstrom, Wilma; Nadel, Dani; Bar-Yosef, Ofer

    2004-01-01

    The beginning of agriculture is one of the most important developments in human history, with enormous consequences that paved the way for settled life and complex society. Much of the research on the origins of agriculture over the last 40 years has been guided by Flannery's [Flannery, K. V. (1969) in The Domestication and Exploitation of Plants and Animals, eds. Ucko, P. J. & Dimbleby, G. W. (Duckworth, London), pp. 73–100] “broad spectrum revolution” (BSR) hypothesis, which posits that the transition to farming in southwest Asia entailed a period during which foragers broadened their resource base to encompass a wide array of foods that were previously ignored in an attempt to overcome food shortages. Although these resources undoubtedly included plants, nearly all BSR hypothesis-inspired research has focused on animals because of a dearth of Upper Paleolithic archaeobotanical assemblages. Now, however, a collection of >90,000 plant remains, recently recovered from the Stone Age site Ohalo II (23,000 B.P.), Israel, offers insights into the plant foods of the late Upper Paleolithic. The staple foods of this assemblage were wild grasses, pushing back the dietary shift to grains some 10,000 years earlier than previously recognized. Besides the cereals (wild wheat and barley), small-grained grasses made up a large component of the assemblage, indicating that the BSR in the Levant was even broader than originally conceived, encompassing what would have been low-ranked plant foods. Over the next 15,000 years small-grained grasses were gradually replaced by the cereals and ultimately disappeared from the Levantine diet. PMID:15210984

  12. Characteristics of doripenem: a new broad-spectrum antibiotic

    Directory of Open Access Journals (Sweden)

    Francisco Alvarez-Lerma

    2009-05-01

    Full Text Available Francisco Alvarez-Lerma1, Santiago Grau2, Olivia Ferrández21Intensive Care Unit, 2Pharmacy Department, Hospital Del Mar, Barcelona, SpainAbstract: Doripenem (S-4661 is a new parenteral antibiotic from the carbapenem class; similarly to imipenem and meropenem, it has a broad-spectrum activity against Gram-positive, Gram-negative, and anaerobic bacteria. It is active against multiresistant Gram-negative bacilli such as extended-spectrum beta-lactamase-producing (ESBL Gram-negative Enterobacteriaceae and nonfermentative Gram-negative bacilli including some strains of Pseudomonas aeruginosa that are resistant to other carbapenems. Doripenem’s chemical structure is similar to that of meropenem (substitution of one sulfamoxil-aminomethyl chain for the dimethyl-carboxyl chain, and has one 1-beta-methyl chain which provides resistance to dehydropeptidase-I enzyme. The clinical trials conducted so far have focused on the treatment of severe infections such as complicated intra-abdominal infections, complicated urinary tract infections and pyelonephritis, nosocomial pneumonia, and ventilator-associated pneumonia. Given its activity profile and the results from the clinical trials, this antibiotic may be used for empirical treatment of multibacterial infections produced by potentially multiresistant Gram-negative bacilli. In 2007, the US Food and Drug Administration approved the use of doripenem for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. The European Medicines Agency has approved the use of doripenem for the same indications in addition to nosocomial pneumonia regardless of whether it is ventilator-associated or not.Keywords: doripenem, antimicrobial activity, clinical efficacy, pharmacokinetics, tolerability

  13. Discovery of potent broad spectrum antivirals derived from marine actinobacteria.

    Directory of Open Access Journals (Sweden)

    Avi Raveh

    Full Text Available Natural products provide a vast array of chemical structures to explore in the discovery of new medicines. Although secondary metabolites produced by microbes have been developed to treat a variety of diseases, including bacterial and fungal infections, to date there has been limited investigation of natural products with antiviral activity. In this report, we used a phenotypic cell-based replicon assay coupled with an iterative biochemical fractionation process to identify, purify, and characterize antiviral compounds produced by marine microbes. We isolated a compound from Streptomyces kaviengensis, a novel actinomycetes isolated from marine sediments obtained off the coast of New Ireland, Papua New Guinea, which we identified as antimycin A1a. This compound displays potent activity against western equine encephalitis virus in cultured cells with half-maximal inhibitory concentrations of less than 4 nM and a selectivity index of greater than 550. Our efforts also revealed that several antimycin A analogues display antiviral activity, and mechanism of action studies confirmed that these Streptomyces-derived secondary metabolites function by inhibiting the cellular mitochondrial electron transport chain, thereby suppressing de novo pyrimidine synthesis. Furthermore, we found that antimycin A functions as a broad spectrum agent with activity against a wide range of RNA viruses in cultured cells, including members of the Togaviridae, Flaviviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Finally, we demonstrate that antimycin A reduces central nervous system viral titers, improves clinical disease severity, and enhances survival in mice given a lethal challenge with western equine encephalitis virus. Our results provide conclusive validation for using natural product resources derived from marine microbes as source material for antiviral drug discovery, and they indicate that host mitochondrial electron transport is a viable

  14. Discovery of potent broad spectrum antivirals derived from marine actinobacteria.

    Science.gov (United States)

    Raveh, Avi; Delekta, Phillip C; Dobry, Craig J; Peng, Weiping; Schultz, Pamela J; Blakely, Pennelope K; Tai, Andrew W; Matainaho, Teatulohi; Irani, David N; Sherman, David H; Miller, David J

    2013-01-01

    Natural products provide a vast array of chemical structures to explore in the discovery of new medicines. Although secondary metabolites produced by microbes have been developed to treat a variety of diseases, including bacterial and fungal infections, to date there has been limited investigation of natural products with antiviral activity. In this report, we used a phenotypic cell-based replicon assay coupled with an iterative biochemical fractionation process to identify, purify, and characterize antiviral compounds produced by marine microbes. We isolated a compound from Streptomyces kaviengensis, a novel actinomycetes isolated from marine sediments obtained off the coast of New Ireland, Papua New Guinea, which we identified as antimycin A1a. This compound displays potent activity against western equine encephalitis virus in cultured cells with half-maximal inhibitory concentrations of less than 4 nM and a selectivity index of greater than 550. Our efforts also revealed that several antimycin A analogues display antiviral activity, and mechanism of action studies confirmed that these Streptomyces-derived secondary metabolites function by inhibiting the cellular mitochondrial electron transport chain, thereby suppressing de novo pyrimidine synthesis. Furthermore, we found that antimycin A functions as a broad spectrum agent with activity against a wide range of RNA viruses in cultured cells, including members of the Togaviridae, Flaviviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Finally, we demonstrate that antimycin A reduces central nervous system viral titers, improves clinical disease severity, and enhances survival in mice given a lethal challenge with western equine encephalitis virus. Our results provide conclusive validation for using natural product resources derived from marine microbes as source material for antiviral drug discovery, and they indicate that host mitochondrial electron transport is a viable target for the

  15. Expansion of a recent class of broad-spectrum antifungal agents: the echinocandins

    Directory of Open Access Journals (Sweden)

    Roberto Manfredi

    2009-09-01

    Full Text Available The echinocandins show comparable efficacy in the treatment of candidemia and invasive candidiasis. Caspofungin and micafungin appear to be similarly efficacious in salvage therapy in aspergillosis; anidulafungin has excellent in vitro activity against Aspergillus species but as yet there are no sufficient clinical data for anidulafungin in this disease state. Each drug has minor advantages and disadvantages compared to the others of the same classe; however, there are large differences in the approved indications for the different drugs. The formulary selection process should consider the direct and indirect costs of the single agents; the characteristics of the patient population at risk for invasive mycosis, such as frequent use of interacting drugs and the burden of monitoring plasma drug levels of drugs; and the implications of using products for indications which have not been still approved (off-label indications.

  16. Broad-spectrum antifungal-producing lactic acid bacteria and their application in fruit models

    National Research Council Canada - National Science Library

    Crowley, Sarah; Mahony, Jennifer; van Sinderen, Douwe

    2013-01-01

    A large-scale screen of some 7,000 presumptive lactic acid bacteria (LAB), isolated from animal, human, or plant origin, identified 1,149 isolates with inhibitory activity against the food-spoilage mould Penicillium expansum...

  17. Synthesis of 2,3,6-trideoxy sugar triazole hybrids as potential new broad spectrum antimicrobial agents.

    Science.gov (United States)

    Sharma, Smriti; Saquib, Mohammad; Verma, Saroj; Mishra, Nripendra N; Shukla, Praveen K; Srivastava, Ranjana; Prabhakar, Yenamandra S; Shaw, Arun K

    2014-08-18

    Here, we describe a molecular hybridization inspired design and synthesis of novel 6-triazolyl 2,3,6-trideoxy sugars as promising new broad-spectrum antimicrobial agents using click chemistry in key step. These compounds showed MIC between 0.39 and 50 μg/mL against different native and resistant bacteria and fungi with no toxicity. Among them, compound 29 was the most active molecule with MIC 0.78 μg/mL against Staphylococcus aureus and Klebsiella pneumoniae and 3.12 μg/mL against methicillin- and vancomycin-resistant S. aureus. Compound 26 was the most potent anti-fungal candidate with MIC 0.39 μg/mL against Trichophyton mentagrophytes. Compound 46 was found to be promising with broad-spectrum activity against both bacterial and fungal strains. The bioinformatic studies involving bacteria's protein co-crystals prompted penicillin binding protein-2 as the most likely target of these compounds.

  18. In vitro studies of BMY-28142, a new broad-spectrum cephalosporin.

    OpenAIRE

    Bodey, G.P.; Ho, D H; Leblanc, B.

    1985-01-01

    BMY-28142 was compared with other broad-spectrum antibiotics against gram-positive cocci and gram-negative bacilli. BMY-28142 was highly active against all gram-negative bacilli and especially against Enterobacter cloacae, Serratia marcescens, and Morganella morganii. Its in vitro activity suggests that BMY-28142 should prove to be useful for the treatment of gram-negative bacillary infections.

  19. Control of helminthosis in lambs by strategic treatment with closantel and broad-spectrum anthelmintics.

    Science.gov (United States)

    Dash, K M

    1986-01-01

    Treatment of ewes with broad-spectrum anthelmintic in August (pre-lambing) and early November, and of lambs in early November and early February, was effective in controlling infections with Trichostrongylus spp in lambs reared on contaminated pastures under set-stocked conditions. It was ineffective in controlling infections with Haemonchus contortus; 82% of lambs had to be withdrawn from the experiment because of severe haemonchosis. Treatment with closantel (7.5 mg/kg) at the same times was very effective against H. contortus but ineffective against Trichostrongylus spp; 25% of lambs had to be withdrawn because of severe trichostrongylosis. The same schedule using broad spectrum anthelmintic and closantel administered concurrently was effective against both parasites; no lambs had to be withdrawn and the bodyweight gain of lambs was higher than in lambs treated with broad-spectrum anthelmintic or closantel alone. The results provide a basis on which to develop a preventive anthelmintic treatment program to control haemonchosis and trichostrongylosis in sheep which will allow the current high frequency of treatment with broad-spectrum anthelmintics to be reduced. Such a program may retard selection for anthelmintic resistance in Trichostrongylus spp.

  20. Draft Genome Sequence of the Broad-Spectrum Xenobiotic Degrader Achromobacter xylosoxidans ADAF13.

    Science.gov (United States)

    Iyer, Rupa; Damania, Ashish

    2016-04-14

    Achromobacter xylosoxidansADAF13, isolated from farmland soil, possesses a large number of putative degradation genes and pathways that break down a wide variety of aromatic hydrocarbons, pesticides, endocrine disruptors, and other high-impact xenobiotics. These properties make this strain an excellent candidate for further development as a broad-spectrum bioremediation agent.

  1. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

    DEFF Research Database (Denmark)

    Taylor, Jenny C; Martin, Hilary C; Lise, Stefano

    2015-01-01

    To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the numb...

  2. Novel water-based antiseptic lotion demonstrates rapid, broad-spectrum kill compared with alcohol antiseptic.

    Science.gov (United States)

    Czerwinski, Steven E; Cozean, Jesse; Cozean, Colette

    2014-01-01

    A novel alcohol-based antiseptic and a novel water-based antiseptic lotion, both with a synergistic combination of antimicrobial ingredients containing 0.2% benzethonium chloride, were evaluated using the standard time-kill method against 25 FDA-specified challenge microorganisms. The purpose of the testing was to determine whether a non-alcohol product could have equivalent rapid and broad-spectrum kill to a traditional alcohol sanitizer. Both the alcohol- and water-based products showed rapid and broad-spectrum antimicrobial activity. The average 15-s kill was 99.999% of the challenge organism for the alcohol-based antiseptic and 99.971% for the water-based antiseptic. The alcohol-based product demonstrated 100% of peak efficacy (60s) within the first 15s, whereas the water-based product showed 99.97%. The novel alcohol-based antiseptic reduced concentrations of 100% of organisms by 99.999%, whereas the water-based antiseptic lotion showed the same reduction for 96% of organisms. A novel water-based antiseptic product demonstrated equivalent rapid, broad-spectrum antimicrobial activity to an alcohol-based sanitizer and provided additional benefits of reduced irritation, persistent effect, and greater efficacy against common viruses. The combination of rapid, broad-spectrum immediate kill and persistent efficacy against pathogens may have significant clinical benefit in limiting the spread of disease.

  3. Broad-Spectrum Antibiotic Treatment and Subsequent Childhood Type 1 Diabetes: A Nationwide Danish Cohort Study

    Science.gov (United States)

    Bergholt, Thomas; Bouaziz, Olivier; Arpi, Magnus; Eriksson, Frank; Rasmussen, Steen; Keiding, Niels; Løkkegaard, Ellen C.

    2016-01-01

    Background Studies link antibiotic treatment and delivery by cesarean section with increased risk of chronic diseases through changes of the gut-microbiota. We aimed to evaluate the association of broad-spectrum antibiotic treatment during the first two years of life with subsequent onset of childhood type 1 diabetes and the potential effect-modification by mode of delivery. Materials and Methods A Danish nationwide cohort study including all singletons born during 1997–2010. End of follow-up by December 2012. Four national registers provided information on antibiotic redemptions, outcome and confounders. Redemptions of antibiotic prescriptions during the first two years of life was classified into narrow-spectrum or broad-spectrum antibiotics. Children were followed from age two to fourteen, both inclusive. The risk of type 1 diabetes with onset before the age of 15 years was assessed by Cox regression. A total of 858,201 singletons contributed 5,906,069 person-years, during which 1,503 children developed type 1 diabetes. Results Redemption of broad-spectrum antibiotics during the first two years of life was associated with an increased rate of type 1 diabetes during the following 13 years of life (HR 1.13; 95% CI 1.02 to 1.25), however, the rate was modified by mode of delivery. Broad-spectrum antibiotics were associated with an increased rate of type 1 diabetes in children delivered by either intrapartum cesarean section (HR 1.70; 95% CI 1.15 to 2.51) or prelabor cesarean section (HR 1.63; 95% CI 1.11 to 2.39), but not in vaginally delivered children. Number needed to harm was 433 and 562, respectively. The association with broad-spectrum antibiotics was not modified by parity, genetic predisposition or maternal redemption of antibiotics during pregnancy or lactation. Conclusions Redemption of broad-spectrum antibiotics during infancy is associated with an increased risk of childhood type 1 diabetes in children delivered by cesarean section. PMID:27560963

  4. Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential.

    Science.gov (United States)

    Zasloff, Michael; Adams, A Paige; Beckerman, Bernard; Campbell, Ann; Han, Ziying; Luijten, Erik; Meza, Isaura; Julander, Justin; Mishra, Abhijit; Qu, Wei; Taylor, John M; Weaver, Scott C; Wong, Gerard C L

    2011-09-20

    Antiviral compounds that increase the resistance of host tissues represent an attractive class of therapeutic. Here, we show that squalamine, a compound previously isolated from the tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus), exhibits broad-spectrum antiviral activity against human pathogens, which were studied in vitro as well as in vivo. Both RNA- and DNA-enveloped viruses are shown to be susceptible. The proposed mechanism involves the capacity of squalamine, a cationic amphipathic sterol, to neutralize the negative electrostatic surface charge of intracellular membranes in a way that renders the cell less effective in supporting viral replication. Because squalamine can be readily synthesized and has a known safety profile in man, we believe its potential as a broad-spectrum human antiviral agent should be explored.

  5. Synthesis and Broad-Spectrum Antiviral Activity of Some Novel Benzo-Heterocyclic Amine Compounds

    Directory of Open Access Journals (Sweden)

    Da-Jun Zhang

    2014-01-01

    Full Text Available A series of novel unsaturated five-membered benzo-heterocyclic amine derivatives were synthesized and assayed to determine their in vitro broad-spectrum antiviral activities. The biological results showed that most of our synthesized compounds exhibited potent broad-spectrum antiviral activity. Notably, compounds 3f (IC50 = 3.21–5.06 μM and 3g (IC50 = 0.71–34.87 μM showed potent activity towards both RNA viruses (influenza A, HCV and Cox B3 virus and a DNA virus (HBV at low micromolar concentrations. An SAR study showed that electron-withdrawing substituents located on the aromatic or heteroaromatic ring favored antiviral activity towards RNA viruses.

  6. The Discussion about Truth Viewpoint and its Significance on the View of Broad-Spectrum Philosophy

    Directory of Open Access Journals (Sweden)

    Facheng Shang

    2012-11-01

    Full Text Available In this study, we have a discussion about truth viewpoint and its significance on the view of Broad-spectrum Philosophy, which inherit and develop the truth of Marxist philosophy Broad-spectrum. Philosophy provides a unique perspective; it introduces the concept of observocontrol mode, which regards the truth as an image in the equivalence class. By changing the observocontrol mode, it reveals “Multilobe” of the truth of the same objective. To answer the question on "how to test the truth", it constructs the procedures and criteria to knowledge the truth. These researches have an important revelation on the enrichment and development of the study of Marxism truth theory.

  7. Broad-Spectrum Antibiotic Treatment and Subsequent Childhood Type 1 Diabetes

    DEFF Research Database (Denmark)

    Clausen, Tine D; Bergholt, Thomas; Bouaziz, Olivier

    2016-01-01

    of childhood type 1 diabetes and the potential effect-modification by mode of delivery. MATERIALS AND METHODS: A Danish nationwide cohort study including all singletons born during 1997-2010. End of follow-up by December 2012. Four national registers provided information on antibiotic redemptions, outcome...... and confounders. Redemptions of antibiotic prescriptions during the first two years of life was classified into narrow-spectrum or broad-spectrum antibiotics. Children were followed from age two to fourteen, both inclusive. The risk of type 1 diabetes with onset before the age of 15 years was assessed by Cox...... regression. A total of 858,201 singletons contributed 5,906,069 person-years, during which 1,503 children developed type 1 diabetes. RESULTS: Redemption of broad-spectrum antibiotics during the first two years of life was associated with an increased rate of type 1 diabetes during the following 13 years...

  8. Broad-spectrum antimicrobial epiphytic and endophytic fungi from marine organisms: isolation, bioassay and taxonomy.

    Science.gov (United States)

    Zhang, Yi; Mu, Jun; Feng, Yan; Kang, Yue; Zhang, Jia; Gu, Peng-Juan; Wang, Yu; Ma, Li-Fang; Zhu, Yan-Hua

    2009-04-17

    In the search for new marine derived antibiotics, 43 epi- and endophytic fungal strains were isolated from the surface or the inner tissue of different marine plants and invertebrates. Through preliminary and secondary screening, 10 of them were found to be able to produce broad-spectrum antimicrobial metabolites. By morphological and molecular biological methods, three active strains were characterized to be Penicillium glabrum, Fusarium oxysporum, and Alternaria alternata.

  9. Broad-Spectrum Antimicrobial Epiphytic and Endophytic Fungi from Marine Organisms: Isolation, Bioassay and Taxonomy

    Directory of Open Access Journals (Sweden)

    Yan-Hua Zhu

    2009-04-01

    Full Text Available In the search for new marine derived antibiotics, 43 epi- and endophytic fungal strains were isolated from the surface or the inner tissue of different marine plants and invertebrates. Through preliminary and secondary screening, 10 of them were found to be able to produce broad-spectrum antimicrobial metabolites. By morphological and molecular biological methods, three active strains were characterized to be Penicillium glabrum, Fusarium oxysporum, and Alternaria alternata.

  10. Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential

    OpenAIRE

    2011-01-01

    Antiviral compounds that increase the resistance of host tissues represent an attractive class of therapeutic. Here, we show that squalamine, a compound previously isolated from the tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus), exhibits broad-spectrum antiviral activity against human pathogens, which were studied in vitro as well as in vivo. Both RNA- and DNA-enveloped viruses are shown to be susceptible. The proposed mechanism involves the capacit...

  11. Brevibacillus laterosporus, a Pathogen of Invertebrates and a Broad-Spectrum Antimicrobial Species

    OpenAIRE

    Luca Ruiu

    2013-01-01

    Brevibacillus laterosporus, a bacterium characterized by the production of a unique canoe-shaped lamellar body attached to one side of the spore, is a natural inhabitant of water, soil and insects. Its biopesticidal potential has been reported against insects in different orders including Coleoptera, Lepidoptera, Diptera and against nematodes and mollusks. In addition to its pathogenicity against invertebrates, different B. laterosporus strains show a broad-spectrum antimicrobial activity inc...

  12. Broad-Spectrum Antimicrobial Epiphytic and Endophytic Fungi from Marine Organisms: Isolation, Bioassay and Taxonomy

    OpenAIRE

    2009-01-01

    In the search for new marine derived antibiotics, 43 epi- and endophytic fungal strains were isolated from the surface or the inner tissue of different marine plants and invertebrates. Through preliminary and secondary screening, 10 of them were found to be able to produce broad-spectrum antimicrobial metabolites. By morphological and molecular biological methods, three active strains were characterized to be Penicillium glabrum, Fusarium oxysporum, and Alternaria alternata.

  13. Broad-spectrum transgenic resistance against distinct tospovirus species at the genus level.

    Directory of Open Access Journals (Sweden)

    Jui-Chu Peng

    Full Text Available Thrips-borne tospoviruses cause severe damage to crops worldwide. In this investigation, tobacco lines transgenic for individual WLm constructs containing the conserved motifs of the L RNA-encoded RNA-dependent RNA polymerase (L gene of Watermelon silver mottle virus (WSMoV were generated by Agrobacterium-mediated transformation. The WLm constructs included: (i translatable WLm in a sense orientation; (ii untranslatable WLmt with two stop codons; (iii untranslatable WLmts with stop codons and a frame-shift; (iv untranslatable antisense WLmA; and (v WLmhp with an untranslatable inverted repeat of WLm containing the tospoviral S RNA 3'-terminal consensus sequence (5'-ATTGCTCT-3' and an NcoI site as a linker to generate a double-stranded hairpin transcript. A total of 46.7-70.0% transgenic tobacco lines derived from individual constructs showed resistance to the homologous WSMoV; 35.7-100% plants of these different WSMoV-resistant lines exhibited broad-spectrum resistance against four other serologically unrelated tospoviruses Tomato spotted wilt virus, Groundnut yellow spot virus, Impatiens necrotic spot virus and Groundnut chlorotic fan-spot virus. The selected transgenic tobacco lines also exhibited broad-spectrum resistance against five additional tospoviruses from WSMoV and Iris yellow spot virus clades, but not against RNA viruses from other genera. Northern analyses indicated that the broad-spectrum resistance is mediated by RNA silencing. To validate the L conserved region resistance in vegetable crops, the constructs were also used to generate transgenic tomato lines, which also showed effective resistance against WSMoV and other tospoviruses. Thus, our approach of using the conserved motifs of tospoviral L gene as a transgene generates broad-spectrum resistance against tospoviruses at the genus level.

  14. Broad spectrum moderators and advanced reflector filters using 208Pb

    OpenAIRE

    Schönfeldt, Troels; Batkov, K.; Klinkby, Esben Bryndt; Lauritzen, Bent; F.Mezei; Muhrer, G.; PITCHER, E; Takibayev, A.; Willendrup, Peter Kjær; Zanini, L.

    2015-01-01

    Cold and thermal neutrons used in neutrons scattering experiments are produced in nuclear reactors and spallation sources. The neutrons are cooled to thermal or cold temperatures in thermal and cold moderators, respectively. The present study shows that it is possible to exploit the poor thermalizing property of 208Pb to design a broad spectrum moderator, i.e. a moderator which emits thermal and cold neutrons from the same position. Using 208Pb as a reflector filter material is shown to be sl...

  15. Antibiotic combination therapy can select for broad-spectrum multidrug resistance in Pseudomonas aeruginosa.

    Science.gov (United States)

    Vestergaard, Martin; Paulander, Wilhelm; Marvig, Rasmus L; Clasen, Julie; Jochumsen, Nicholas; Molin, Søren; Jelsbak, Lars; Ingmer, Hanne; Folkesson, Anders

    2016-01-01

    Combination therapy with several antibiotics is one strategy that has been applied in order to limit the spread of antimicrobial resistance. We compared the de novo evolution of resistance during combination therapy with the β-lactam ceftazidime and the fluoroquinolone ciprofloxacin with the resistance evolved after single-drug exposure. Combination therapy selected for mutants that displayed broad-spectrum resistance, and a major resistance mechanism was mutational inactivation of the repressor gene mexR that regulates the multidrug efflux operon mexAB-oprM. Deregulation of this operon led to a broad-spectrum resistance phenotype that decreased susceptibility to the combination of drugs applied during selection as well as to unrelated antibiotic classes. Mutants isolated after single-drug exposure displayed narrow-spectrum resistance and carried mutations in the MexCD-OprJ efflux pump regulator gene nfxB conferring ciprofloxacin resistance, or in the gene encoding the non-essential penicillin-binding protein DacB conferring ceftazidime resistance. Reconstruction of resistance mutations by allelic replacement and in vitro fitness assays revealed that in contrast to single antibiotic use, combination therapy consistently selected for mutants with enhanced fitness expressing broad-spectrum resistance mechanisms.

  16. A comparison of effects of broad-spectrum antibiotics and biosurfactants on established bacterial biofilms.

    Science.gov (United States)

    Quinn, Gerry A; Maloy, Aaron P; Banat, Malik M; Banat, Ibrahim M

    2013-11-01

    Current antibiofilm solutions based on planktonic bacterial physiology have limited efficacy in clinical and occasionally environmental settings. This has prompted a search for suitable alternatives to conventional therapies. This study compares the inhibitory properties of two biological surfactants (rhamnolipids and a plant-derived surfactant) against a selection of broad-spectrum antibiotics (ampicillin, chloramphenicol and kanamycin). Testing was carried out on a range of bacterial physiologies from planktonic and mixed bacterial biofilms. Rhamnolipids (Rhs) have been extensively characterised for their role in the development of biofilms and inhibition of planktonic bacteria. However, there are limited direct comparisons with antimicrobial substances on established biofilms comprising single or mixed bacterial strains. Baseline measurements of inhibitory activity using planktonic bacterial assays established that broad-spectrum antibiotics were 500 times more effective at inhibiting bacterial growth than either Rhs or plant surfactants. Conversely, Rhs and plant biosurfactants reduced biofilm biomass of established single bacterial biofilms by 74-88 and 74-98 %, respectively. Only kanamycin showed activity against biofilms of Bacillus subtilis and Staphylococcus aureus. Broad-spectrum antibiotics were also ineffective against a complex biofilm of marine bacteria; however, Rhs and plant biosurfactants reduced biofilm biomass by 69 and 42 %, respectively. These data suggest that Rhs and plant-derived surfactants may have an important role in the inhibition of complex biofilms.

  17. Isolation and Preliminary Characterization of Proteinaceous Toxins with Insecticidal and Antibacterial Activities from Black Widow Spider (L. tredecimguttatus Eggs

    Directory of Open Access Journals (Sweden)

    Qian Lei

    2015-03-01

    Full Text Available The eggs of black widow spider (L. tredecimguttatus have been demonstrated to be rich in toxic proteinaceous components. The study on such active components is of theoretical and practical importance. In the present work, using a combination of multiple biochemical and biological strategies, we isolated and characterized the proteinaceous components from the aqueous extract of the black widow spider eggs. After gel filtration of the egg extract, the resulting main protein and peptide peaks were further fractionated by ion exchange chromatography and reversed-phase high performance liquid chromatography. Two proteinaceous components, named latroeggtoxin-III and latroeggtoxin-IV, respectively, were purified to homogeneity. Latroeggtoxin-III was demonstrated to have a molecular weight of about 36 kDa. Activity analysis indicated that latroeggtoxin-III exhibited neurotoxicity against cockroaches but had no obvious effect on mice, suggesting that it is an insect-specific toxin. Latroeggtoxin-IV, with a molecular weight of 3.6 kDa, was shown to be a broad-spectrum antibacterial peptide, showing inhibitory activity against all five species of bacteria tested, with the highest activity against Staphylococcus aureus. Finally, the implications of the proteinaceous toxins in egg protection and their potential applications were analyzed and discussed.

  18. Broad spectrum antiviral activity of favipiravir (T-705: protection from highly lethal inhalational Rift Valley Fever.

    Directory of Open Access Journals (Sweden)

    Amy L Caroline

    2014-04-01

    Full Text Available BACKGROUND: Development of antiviral drugs that have broad-spectrum activity against a number of viral infections would be of significant benefit. Due to the evolution of resistance to currently licensed antiviral drugs, development of novel anti-influenza drugs is in progress, including Favipiravir (T-705, which is currently in human clinical trials. T-705 displays broad-spectrum in vitro activity against a number of viruses, including Rift Valley Fever virus (RVFV. RVF is an important neglected tropical disease that causes human, agricultural, and economic losses in endemic regions. RVF has the capacity to emerge in new locations and also presents a potential bioterrorism threat. In the current study, the in vivo efficacy of T-705 was evaluated in Wistar-Furth rats infected with the virulent ZH501 strain of RVFV by the aerosol route. METHODOLOGY/PRINCIPAL FINDINGS: Wistar-Furth rats are highly susceptible to a rapidly lethal disease after parenteral or inhalational exposure to the pathogenic ZH501 strain of RVFV. In the current study, two experiments were performed: a dose-determination study and a delayed-treatment study. In both experiments, all untreated control rats succumbed to disease. Out of 72 total rats infected with RVFV and treated with T-705, only 6 succumbed to disease. The remaining 66 rats (92% survived lethal infection with no significant weight loss or fever. The 6 treated rats that succumbed survived significantly longer before succumbing to encephalitic disease. CONCLUSIONS/SIGNIFICANCE: Currently, there are no licensed antiviral drugs for treating RVF. Here, T-705 showed remarkable efficacy in a highly lethal rat model of Rift Valley Fever, even when given up to 48 hours post-infection. This is the first study to show protection of rats infected with the pathogenic ZH501 strain of RVFV. Our data suggest that T-705 has potential to be a broad-spectrum antiviral drug.

  19. In vitro assessment of the broad-spectrum ultraviolet protection of sunscreen products.

    Science.gov (United States)

    Diffey, B L; Tanner, P R; Matts, P J; Nash, J F

    2000-12-01

    There are considerable data to suggest that protection from solar ultraviolet (UV) radiation will reduce the risk of acute and chronic skin damage in humans. Whereas the sun protection factor (SPF) provides an index of protection against erythemally effective solar UV, largely confined to the UVB (290-320 nm) and short-wavelength UVA (320-340 nm) region, there is currently no agreed-upon method to measure broad-spectrum protection against long-wavelength UVA (340-400 nm). The objective of these studies was to assess the potential of in vitro UV substrate spectrophotometry and subsequent calculation of the "critical wavelength" value as a measure of broad-spectrum UV protection and as a routine, practical procedure for classification of sunscreen products. The spectral absorption of 59 commercially available sunscreen products and multiple experimental formulas with one or more UV filters was measured. Sunscreen product, 1 mg/cm(2), was applied to a hydrated synthetic collagen substrate, preirradiated with a solar simulator, and then subjected to UV substrate spectrophotometry. Multiple determinations from 5 independent samples per product were used to calculate the critical wavelength value, defined as the wavelength at which the integral of the spectral absorbance curve reached 90% of the integral from 290 to 400 nm. We found that a recognized long-wave UVA active ingredient such as titanium dioxide, zinc oxide, or avobenzone is a necessary but insufficient product requirement for achieving the highest proposed broad-spectrum classification, that is, critical wavelength of 370 nm or more. Although SPF and critical wavelength are largely independent of each other, UVA absorbance must increase commensurate with SPF to maintain the same critical wavelength value. Substrate spectrophotometry and the calculation of critical wavelength can readily account for sunscreen photostability by UV preirradiation. Finally, there is also a strong positive relationship between

  20. Nanomedicine for Infectious Disease Applications: Innovation towards Broad-Spectrum Treatment of Viral Infections.

    Science.gov (United States)

    Jackman, Joshua A; Lee, Jaywon; Cho, Nam-Joon

    2016-03-02

    Nanomedicine enables unique diagnostic and therapeutic capabilities to tackle problems in clinical medicine. As multifunctional agents with programmable properties, nanomedicines are poised to revolutionize treatment strategies. This promise is especially evident for infectious disease applications, for which the continual emergence, re-emergence, and evolution of pathogens has proven difficult to counter by conventional approaches. Herein, a conceptual framework is presented that envisions possible routes for the development of nanomedicines as superior broad-spectrum antiviral agents against enveloped viruses. With lipid membranes playing a critical role in the life cycle of medically important enveloped viruses including HIV, influenza, and Ebola, cellular and viral membrane interfaces are ideal elements to incorporate into broad-spectrum antiviral strategies. Examples are presented that demonstrate how nanomedicine strategies inspired by lipid membranes enable a wide range of targeting opportunities to gain control of critical stages in the virus life cycle through either direct or indirect approaches involving membrane interfaces. The capabilities can be realized by enabling new inhibitory functions or improving the function of existing drugs through nanotechnology-enabled solutions. With these exciting opportunities, due attention is also given to the clinical translation of nanomedicines for infectious disease applications, especially as pharmaceutical drug-discovery pipelines demand new routes of innovation.

  1. Towards establishing broad-spectrum disease resistance in plants: silicon leads the way.

    Science.gov (United States)

    Van Bockhaven, Jonas; De Vleesschauwer, David; Höfte, Monica

    2013-03-01

    Plants are constantly threatened by a wide array of microbial pathogens. Pathogen invasion can lead to vast yield losses and the demand for sustainable plant-protection strategies has never been greater. Chemical plant activators and selected strains of rhizobacteria can increase resistance against specific types of pathogens but these treatments are often ineffective or even cause susceptibility against others. Silicon application is one of the scarce examples of a treatment that effectively induces broad-spectrum disease resistance. The prophylactic effect of silicon is considered to be the result of both passive and active defences. Although the phenomenon has been known for decades, very little is known about the molecular basis of silicon-afforded disease control. By combining knowledge on how silicon interacts with cell metabolism in diatoms and plants, this review describes silicon-induced regulatory mechanisms that might account for broad-spectrum plant disease resistance. Priming of plant immune responses, alterations in phytohormone homeostasis, regulation of iron homeostasis, silicon-driven photorespiration and interaction with defence signalling components all are potential mechanisms involved in regulating silicon-triggered resistance responses. Further elucidating how silicon exerts its beneficial properties may create new avenues for developing plants that are better able to withstand multiple attackers.

  2. Identification and Structural Characterization of Naturally-Occurring Broad-Spectrum Cyclic Antibiotics Isolated from Paenibacillus

    Science.gov (United States)

    Knolhoff, Ann M.; Zheng, Jie; McFarland, Melinda A.; Luo, Yan; Callahan, John H.; Brown, Eric W.; Croley, Timothy R.

    2015-08-01

    The rise of antimicrobial resistance necessitates the discovery and/or production of novel antibiotics. Isolated strains of Paenibacillus alvei were previously shown to exhibit antimicrobial activity against a number of pathogens, such as E. coli, Salmonella, and methicillin-resistant Staphylococcus aureus (MRSA). The responsible antimicrobial compounds were isolated from these Paenibacillus strains and a combination of low and high resolution mass spectrometry with multiple-stage tandem mass spectrometry was used for identification. A group of closely related cyclic lipopeptides was identified, differing primarily by fatty acid chain length and one of two possible amino acid substitutions. Variation in the fatty acid length resulted in mass differences of 14 Da and yielded groups of related MSn spectra. Despite the inherent complexity of MS/MS spectra of cyclic compounds, straightforward analysis of these spectra was accomplished by determining differences in complementary product ion series between compounds that differ in molecular weight by 14 Da. The primary peptide sequence assignment was confirmed through genome mining; the combination of these analytical tools represents a workflow that can be used for the identification of complex antibiotics. The compounds also share amino acid sequence similarity to a previously identified broad-spectrum antibiotic isolated from Paenibacillus. The presence of such a wide distribution of related compounds produced by the same organism represents a novel class of broad-spectrum antibiotic compounds.

  3. Analysis of mobile health applications for a broad spectrum of consumers: a user experience approach.

    Science.gov (United States)

    García-Gómez, Juan M; de la Torre-Díez, Isabel; Vicente, Javier; Robles, Montserrat; López-Coronado, Miguel; Rodrigues, Joel J

    2014-03-01

    Mobile health (m-health) apps can bring health prevention and promotion to the general population. The main purpose of this article is to analyze different m-health apps for a broad spectrum of consumers by means of three different experiences. This goal was defined following the strategic documents generated by the main prospective observatories of Information and Communications Technology for health. After a general exploration of the app markets, we analyze the entries of three specific themes focused in this article: type 2 diabetes, obesity, and breast-feeding. The user experiences reported in this study mostly cover the segments of (1) chronically monitored consumers through a Web mobile app for predicting type 2 diabetes (Diab_Alert app), (2) information seekers through a mobile app for maternity (Lactation app) and partially (3) the motivated healthy consumers through a mobile app for a dietetic monitoring and assessment (SapoFit app). These apps were developed by the authors of this work.

  4. Synergistic effect of broad-spectrum Sunscreens and antihistamines in the control of idiopathic solar urticaria

    DEFF Research Database (Denmark)

    Faurschou, A.; Wulf, Hans Chr.

    2008-01-01

    Background: It can be difficult to provide patients with idiopathic solar urticaria adequate protection from sunlight. In a nonrandomized controlled trial, we used a standardized phototest procedure to determine the effects of using sunscreen and antihistamine to control idiopathic solar urticaria....... The patients were then treated with a high-protection, broad-spectrum sunscreen and a nonsedative antihistamine alone and in combination and underwent similar phototesting. The use of sunscreen allowed the patients to tolerate much higher doses of UV radiation (32-38 times the MUD on untreated skin......). Antihistamine use did not increase the patients' MUD but did suppress wheal formation and itch, and only immediate erythema sharply located in the irradiated areas occurred. The combination of sunscreen and antihistamine acted synergistically and increased the tolerance to UV radiation markedly (80-267 times...

  5. Multilayer nanoparticle arrays for broad spectrum absorption enhancement in thin film solar cells

    CERN Document Server

    Krishnan, Aravind; Krishna, Siva Rama; Khan, Mohammed Zafar Ali

    2013-01-01

    In this paper, we present a theoretical study on the absorption efficiency enhancement of a thin film amorphous Silicon (a-Si) photovoltaic cell over a broad spectrum of wavelengths using multiple nanoparticle arrays. The light absorption efficiency is enhanced in the lower wavelengths by a nanoparticle array on the surface and in the higher wavelengths by another nanoparticle array embedded in the active region. The efficiency at intermediate wavelengths is enhanced by the constructive interference of plasmon coupled light. We optimize this design by tuning the radius of particles in both arrays, the period of the array and the distance between the two arrays. The optimization results in 61.44% increase in total quantum efficiency for a 500 nm thick a-Si substrate.

  6. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases

    Science.gov (United States)

    Dinarello, Charles A.; Simon, Anna; van der Meer, Jos W. M.

    2013-01-01

    Interleukin-1 (IL-1) is a highly active pro-inflammatory cytokine that lowers pain thresholds and damages tissues. Monotherapy blocking IL-1 activity in autoinflammatory syndromes results in a rapid and sustained reduction in disease severity, including reversal of inflammation-mediated loss of sight, hearing and organ function. This approach can therefore be effective in treating common conditions such as post-infarction heart failure, and trials targeting a broad spectrum of new indications are underway. So far, three IL-1-targeted agents have been approved: the IL-1 receptor antagonist anakinra, the soluble decoy receptor rilonacept and the neutralizing monoclonal anti-IL-1β antibody canakinumab. In addition, a monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1α antibody are in clinical trials. PMID:22850787

  7. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

    Science.gov (United States)

    Lise, Stefano; Broxholme, John; Cazier, Jean-Baptiste; Rimmer, Andy; Kanapin, Alexander; Lunter, Gerton; Fiddy, Simon; Allan, Chris; Aricescu, A. Radu; Attar, Moustafa; Babbs, Christian; Becq, Jennifer; Beeson, David; Bento, Celeste; Bignell, Patricia; Blair, Edward; Buckle, Veronica J; Bull, Katherine; Cais, Ondrej; Cario, Holger; Chapel, Helen; Copley, Richard R; Cornall, Richard; Craft, Jude; Dahan, Karin; Davenport, Emma E; Dendrou, Calliope; Devuyst, Olivier; Fenwick, Aimée L; Flint, Jonathan; Fugger, Lars; Gilbert, Rodney D; Goriely, Anne; Green, Angie; Greger, Ingo H.; Grocock, Russell; Gruszczyk, Anja V; Hastings, Robert; Hatton, Edouard; Higgs, Doug; Hill, Adrian; Holmes, Chris; Howard, Malcolm; Hughes, Linda; Humburg, Peter; Johnson, David; Karpe, Fredrik; Kingsbury, Zoya; Kini, Usha; Knight, Julian C; Krohn, Jonathan; Lamble, Sarah; Langman, Craig; Lonie, Lorne; Luck, Joshua; McCarthy, Davis; McGowan, Simon J; McMullin, Mary Frances; Miller, Kerry A; Murray, Lisa; Németh, Andrea H; Nesbit, M Andrew; Nutt, David; Ormondroyd, Elizabeth; Oturai, Annette Bang; Pagnamenta, Alistair; Patel, Smita Y; Percy, Melanie; Petousi, Nayia; Piazza, Paolo; Piret, Sian E; Polanco-Echeverry, Guadalupe; Popitsch, Niko; Powrie, Fiona; Pugh, Chris; Quek, Lynn; Robbins, Peter A; Robson, Kathryn; Russo, Alexandra; Sahgal, Natasha; van Schouwenburg, Pauline A; Schuh, Anna; Silverman, Earl; Simmons, Alison; Sørensen, Per Soelberg; Sweeney, Elizabeth; Taylor, John; Thakker, Rajesh V; Tomlinson, Ian; Trebes, Amy; Twigg, Stephen RF; Uhlig, Holm H; Vyas, Paresh; Vyse, Tim; Wall, Steven A; Watkins, Hugh; Whyte, Michael P; Witty, Lorna; Wright, Ben; Yau, Chris; Buck, David; Humphray, Sean; Ratcliffe, Peter J; Bell, John I; Wilkie, Andrew OM; Bentley, David; Donnelly, Peter; McVean, Gilean

    2015-01-01

    To assess factors influencing the success of whole genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases across a broad spectrum of disorders in whom prior screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritisation. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease causing variants in 21% of cases, rising to 34% (23/68) for Mendelian disorders and 57% (8/14) in trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, though only four were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis, but also highlight many outstanding challenges. PMID:25985138

  8. Interfamily transfer of a plant pattern-recognition receptor confers broad-spectrum bacterial resistance.

    Science.gov (United States)

    Lacombe, Séverine; Rougon-Cardoso, Alejandra; Sherwood, Emma; Peeters, Nemo; Dahlbeck, Douglas; van Esse, H Peter; Smoker, Matthew; Rallapalli, Ghanasyam; Thomma, Bart P H J; Staskawicz, Brian; Jones, Jonathan D G; Zipfel, Cyril

    2010-04-01

    Plant diseases cause massive losses in agriculture. Increasing the natural defenses of plants may reduce the impact of phytopathogens on agricultural productivity. Pattern-recognition receptors (PRRs) detect microbes by recognizing conserved pathogen-associated molecular patterns (PAMPs). Although the overall importance of PAMP-triggered immunity for plant defense is established, it has not been used to confer disease resistance in crops. We report that activity of a PRR is retained after its transfer between two plant families. Expression of EFR (ref. 4), a PRR from the cruciferous plant Arabidopsis thaliana, confers responsiveness to bacterial elongation factor Tu in the solanaceous plants Nicotiana benthamiana and tomato (Solanum lycopersicum), making them more resistant to a range of phytopathogenic bacteria from different genera. Our results in controlled laboratory conditions suggest that heterologous expression of PAMP recognition systems could be used to engineer broad-spectrum disease resistance to important bacterial pathogens, potentially enabling more durable and sustainable resistance in the field.

  9. The Arabidopsis NPR1 gene confers broad-spectrum disease resistance in strawberry.

    Science.gov (United States)

    Silva, Katchen Julliany P; Brunings, Asha; Peres, Natalia A; Mou, Zhonglin; Folta, Kevin M

    2015-08-01

    Although strawberry is an economically important fruit crop worldwide, production of strawberry is limited by its susceptibility to a wide range of pathogens and the lack of major commercial cultivars with high levels of resistance to multiple pathogens. The objective of this study is to ectopically express the Arabidopsis thaliana NPR1 gene (AtNPR1) in the diploid strawberry Fragaria vesca L. and to test transgenic plants for disease resistance. AtNPR1 is a key positive regulator of the long-lasting broad-spectrum resistance known as systemic acquired resistance (SAR) and has been shown to confer resistance to a number of pathogens when overexpressed in Arabidopsis or ectopically expressed in several crop species. We show that ectopic expression of AtNPR1 in strawberry increases resistance to anthracnose, powdery mildew, and angular leaf spot, which are caused by different fungal or bacterial pathogens. The increased resistance is related to the relative expression levels of AtNPR1 in the transgenic plants. In contrast to Arabidopsis plants overexpressing AtNPR1, which grow normally and do not constitutively express defense genes, the strawberry transgenic plants are shorter than non-transformed controls, and most of them fail to produce runners and fruits. Consistently, most of the transgenic lines constitutively express the defense gene FvPR5, suggesting that the SAR activation mechanisms in strawberry and Arabidopsis are different. Nevertheless, our results indicate that overexpression of AtNPR1 holds the potential for generation of broad-spectrum disease resistance in strawberry.

  10. Immune Responses to Broad-Spectrum Antibiotic Treatment and Fecal Microbiota Transplantation in Mice

    Science.gov (United States)

    Ekmekciu, Ira; von Klitzing, Eliane; Fiebiger, Ulrike; Escher, Ulrike; Neumann, Christian; Bacher, Petra; Scheffold, Alexander; Kühl, Anja A.; Bereswill, Stefan; Heimesaat, Markus M.

    2017-01-01

    Compelling evidence demonstrates the pivotal role of the commensal intestinal microbiota in host physiology and the detrimental effects of its perturbations following antibiotic treatment. Aim of this study was to investigate the impact of antibiotics induced depletion and subsequent restoration of the intestinal microbiota composition on the murine mucosal and systemic immunity. To address this, conventional C57BL/6j mice were subjected to broad-spectrum antibiotic treatment for 8 weeks. Restoration of the intestinal microbiota by peroral fecal microbiota transplantation (FMT) led to reestablishment of small intestinal CD4+, CD8+, and B220+ as well as of colonic CD4+ cell numbers as early as 7 days post-FMT. However, at d28 following FMT, colonic CD4+ and B220+ cell numbers were comparable to those in secondary abiotic (ABx) mice. Remarkably, CD8+ cell numbers were reduced in the colon upon antibiotic treatment, and FMT was not sufficient to restore this immune cell subset. Furthermore, absence of gut microbial stimuli resulted in decreased percentages of memory/effector T cells, regulatory T cells, and activated dendritic cells in the small intestine, colon, mesenteric lymph nodes (MLN), and spleen. Concurrent antibiotic treatment caused decreased cytokine production (IFN-γ, IL-17, IL-22, and IL-10) of CD4+ cells in respective compartments. These effects were, however, completely restored upon FMT. In summary, broad-spectrum antibiotic treatment resulted in profound local (i.e., small and large intestinal), peripheral (i.e., MLN), and systemic (i.e., splenic) changes in the immune cell repertoire that could, at least in part, be restored upon FMT. Further studies need to unravel the distinct molecular mechanisms underlying microbiota-driven changes in immune homeostasis subsequently providing novel therapeutic or even preventive approaches in human immunopathologies. PMID:28469619

  11. A robust, single-injection method for targeted, broad-spectrum plasma metabolomics.

    Science.gov (United States)

    Li, Kefeng; Naviaux, Jane C; Bright, A Taylor; Wang, Lin; Naviaux, Robert K

    2017-01-01

    Metabolomics is a powerful emerging technology for studying the systems biology and chemistry of health and disease. Current targeted methods are often limited by the number of analytes that can be measured, and/or require multiple injections. We developed a single-injection, targeted broad-spectrum plasma metabolomic method on a SCIEX Qtrap 5500 LC-ESI-MS/MS platform. Analytical validation was conducted for the reproducibility, linearity, carryover and blood collection tube effects. The method was also clinically validated for its potential utility in the diagnosis of chronic fatigue syndrome (CFS) using a cohort of 22 males CFS and 18 age- and sex-matched controls. Optimization of LC conditions and MS/MS parameters enabled the measurement of 610 key metabolites from 63 biochemical pathways and 95 stable isotope standards in a 45-minute HILIC method using a single injection without sacrificing sensitivity. The total imprecision (CVtotal) of peak area was 12% for both the control and CFS pools. The 8 metabolites selected in our previous study (PMID: 27573827) performed well in a clinical validation analysis even when the case and control samples were analyzed 1.5 years later on a different instrument by a different investigator, yielding a diagnostic accuracy of 95% (95% CI 85-100%) measured by the area under the ROC curve. A reliable and reproducible, broad-spectrum, targeted metabolomic method was developed, capable of measuring over 600 metabolites in plasma in a single injection. The method might be a useful tool in helping the diagnosis of CFS or other complex diseases.

  12. Surveillance of broad-spectrum antibiotic prescription in Singaporean hospitals: a 5-year longitudinal study.

    Directory of Open Access Journals (Sweden)

    Yi-Xin Liew

    Full Text Available BACKGROUND: Inappropriate prescription of antibiotics may contribute towards higher levels antimicrobial resistance. A key intervention for improving appropriate antibiotic prescription is surveillance of prescription. This paper presents the results of a longitudinal surveillance of broad-spectrum antibiotic prescription in 5 public-sector hospitals in Singapore from 2006 to 2010. METHODOLOGY/PRINCIPAL FINDINGS: Quarterly antibiotic prescription data were obtained and converted to defined daily doses (DDDs per 1,000 inpatient-days. The presence of significant trends in antibiotic prescription over time for both individual and combined hospitals was tested by regression analysis and corrected for autocorrelation between time-points. Excluding fluoroquinolones, there was a significant increase in prescription of all monitored antibiotics from an average of 233.12 defined daily doses (DDD/1,000 inpatient-days in 2006 to 254.38 DDD/1,000 inpatient-days in 2010 (Coefficient = 1.13, 95%CI: 0.16-2.09, p = 0.025. Increasing utilization of carbapenems, piperacillin/tazobactam, and Gram-positive agents were seen in the majority of the hospitals, while cephalosporins were less prescribed over time. The combined expenditure for 5 hospitals increased from USD9.9 million in 2006 to USD16.7 million in 2010. CONCLUSIONS/SIGNIFICANCE: The rate of prescription of broad-spectrum antibiotics in Singaporean hospitals is much higher compared to those of European hospitals. This may be due to high rates of antimicrobial resistance. The increase in expenditure on monitored antibiotics over the past 5 years outstripped the actual increase in DDD/1,000 inpatient-days of antibiotics prescribed. Longitudinal surveillance of antibiotic prescription on a hospital and countrywide level is important for detecting trends for formulating interventions or policies. Further research is needed to understand the causes for the various prescription trends and to act on these where

  13. Trends in broad-spectrum antibiotic prescribing for children with acute otitis media in the United States, 1998–2004

    Directory of Open Access Journals (Sweden)

    Gambler Angela S

    2009-06-01

    Full Text Available Abstract Background Overuse of broad-spectrum antibiotics is associated with antibiotic resistance. Acute otitis media (AOM is responsible for a large proportion of antibiotics prescribed for US children. Rates of broad-spectrum antibiotic prescribing for AOM are unknown. Methods Analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, 1998 to 2004 (N = 6,878. Setting is office-based physicians, hospital outpatient departments, and emergency departments. Patients are children aged 12 years and younger prescribed antibiotics for acute otitis media. Main outcome measure is percentage of broad-spectrum antibiotics, defined as amoxicillin/clavulanate, macrolides, cephalosporins and quinolones. Results Broad-spectrum prescribing for acute otitis media increased from 34% of visits in 1998 to 45% of visits in 2004 (P Conclusion Prescribing of broad-spectrum antibiotics for acute otitis media has steadily increased from 1998 to 2004. Associations with non-clinical factors suggest potential for improvement in prescribing practice.

  14. Pharmacokinetics and pharmacodynamics of ceftobiprole, an anti-MRSA cephalosporin with broad-spectrum activity.

    Science.gov (United States)

    Murthy, Bindu; Schmitt-Hoffmann, Anne

    2008-01-01

    Ceftobiprole, a beta-lactam, is the first of a new generation of broad-spectrum cephalosporins in late-stage development with activity against methicillin-resistant Staphylococcus aureus (MRSA) in addition to broad-spectrum bactericidal activity against other Gram-positive and Gram-negative pathogens. The prodrug, ceftobiprole medocaril, is converted rapidly and almost completely to the active drug, ceftobiprole, upon infusion by type A esterases. In humans, ceftobiprole binds minimally (16%) to plasma proteins, and binding is independent of the drug and protein concentrations. Its steady-state volume of distribution (18.4 L) approximates the extracellular fluid volume in humans. Ceftobiprole undergoes minimal hepatic metabolism, and the primary metabolite is the beta-lactam ring-opened hydrolysis product (open-ring metabolite). Systemic exposure of the open-ring metabolite accounts for 4% of ceftobiprole exposure following single-dose administration; approximately 5% of the dose is excreted in the urine as the metabolite. Ceftobiprole does not significantly induce or inhibit relevant cytochrome P450 enzymes and is neither a substrate nor an inhibitor of P-glycoprotein. Ceftobiprole is rapidly eliminated, primarily unchanged, by renal excretion, with a terminal elimination half-life of 3 hours; the predominant mechanism responsible for elimination is glomerular filtration, with approximately 89% of the dose being excreted as the prodrug, active drug (ceftobiprole) and open-ring metabolite. The pharmacokinetics of ceftobiprole are linear following single and multiple infusions of 125-1000 mg. Steady-state drug concentrations are attained on the first day of dosing, with no appreciable accumulation when administered three times daily (every 8 hours) and twice daily (every 12 hours) in subjects with normal renal function. Low intersubject variability has been seen across studies. Ceftobiprole exposure is slightly higher (~15%) in females than in males; this difference

  15. Development of broad-spectrum antimicrobial latex paint surfaces employing active amphiphilic compounds.

    Science.gov (United States)

    Fulmer, Preston A; Wynne, James H

    2011-08-01

    With the increase in antibiotic-resistant microbes, the production of self-decontaminating surfaces has become an area of research that has seen a surge of interest in recent years. Such surfaces, when incorporated into commercial products such as children's toys, medical devices and hospital surfaces could reduce the number of infections caused by pathogenic microorganisms. A number of active components for self-decontaminating surfaces have been investigated, including common antibiotics, metal ions, quaternary ammonium salts (QAS), and antimicrobial peptides (AMP). A recent research focus has been development of a wide range of amphiphilic antimicrobial additives that when combined with modern low volatile organic compound (VOC), water-based paints leads to a surface concentration of the active compounds as the coating cures. Herein we report the development of antimicrobial coatings containing a variety of additives, both QAS and AMP that are active against a broad-spectrum of potentially pathogenic bacteria (1-7 log kill), as well as enveloped viruses (2-7 log kill) and fungi (1-2 log kill). Additionally, these additives were compatible with water-dispersed acrylate coatings (latex paint) which have a broad range of real world applicability, and remained active for multiple challenges and when exposed to various cleaning scenarios in which they might encounter in real world situations.

  16. Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents.

    Science.gov (United States)

    Brai, Annalaura; Fazi, Roberta; Tintori, Cristina; Zamperini, Claudio; Bugli, Francesca; Sanguinetti, Maurizio; Stigliano, Egidio; Esté, José; Badia, Roger; Franco, Sandra; Martinez, Miguel A; Martinez, Javier P; Meyerhans, Andreas; Saladini, Francesco; Zazzi, Maurizio; Garbelli, Anna; Maga, Giovanni; Botta, Maurizio

    2016-05-10

    Targeting a host factor essential for the replication of different viruses but not for the cells offers a higher genetic barrier to the development of resistance, may simplify therapy regimens for coinfections, and facilitates management of emerging viral diseases. DEAD-box polypeptide 3 (DDX3) is a human host factor required for the replication of several DNA and RNA viruses, including some of the most challenging human pathogens currently circulating, such as HIV-1, Hepatitis C virus, Dengue virus, and West Nile virus. Herein, we showed for the first time, to our knowledge, that the inhibition of DDX3 by a small molecule could be successfully exploited for the development of a broad spectrum antiviral agent. In addition to the multiple antiviral activities, hit compound 16d retained full activity against drug-resistant HIV-1 strains in the absence of cellular toxicity. Pharmacokinetics and toxicity studies in rats confirmed a good safety profile and bioavailability of 16d. Thus, DDX3 is here validated as a valuable therapeutic target.

  17. Tempered mlo broad-spectrum resistance to barley powdery mildew in an Ethiopian landrace.

    Science.gov (United States)

    Ge, Xintian; Deng, Weiwei; Lee, Zheng Zhou; Lopez-Ruiz, Francisco J; Schweizer, Patrick; Ellwood, Simon R

    2016-07-12

    Recessive mutations in the Mlo gene confer broad spectrum resistance in barley (Hordeum vulgare) to powdery mildew (Blumeria graminis f. sp. hordei), a widespread and damaging disease. However, all alleles discovered to date also display deleterious pleiotropic effects, including the naturally occurring mlo-11 mutant which is widely deployed in Europe. Recessive resistance was discovered in Eth295, an Ethiopian landrace, which was developmentally controlled and quantitative without spontaneous cell wall appositions or extensive necrosis and loss of photosynthetic tissue. This resistance is determined by two copies of the mlo-11 repeat units, that occur upstream to the wild-type Mlo gene, compared to 11-12 in commonly grown cultivars and was designated mlo-11 (cnv2). mlo-11 repeat unit copy number-dependent DNA methylation corresponded with cytological and macroscopic phenotypic differences between copy number variants. Sequence data indicated mlo-11 (cnv2) formed via recombination between progenitor mlo-11 repeat units and the 3' end of an adjacent stowaway MITE containing region. mlo-11 (cnv2) is the only example of a moderated mlo variant discovered to date and may have arisen by natural selection against the deleterious effects of the progenitor mlo-11 repeat unit configuration.

  18. Arbidol: a broad-spectrum antiviral that inhibits acute and chronic HCV infection

    Directory of Open Access Journals (Sweden)

    Pécheur Eve-Isabelle

    2006-07-01

    Full Text Available Abstract Arbidol (ARB is an antiviral compound that was originally proven effective for treatment of influenza and several other respiratory viral infections. The broad spectrum of ARB anti-viral activity led us to evaluate its effect on hepatitis C virus (HCV infection and replication in cell culture. Long-term ARB treatment of Huh7 cells chronically replicating a genomic length genotype 1b replicon resulted in sustained reduction of viral RNA and protein expression, and eventually cured HCV infected cells. Pre-treatment of human hepatoma Huh7.5.1 cells with 15 μM ARB for 24 to 48 hours inhibited acute infection with JFH-1 virus by up to 1000-fold. The inhibitory effect of ARB on HCV was not due to generalized cytotoxicity, nor to augmentation of IFN antiviral signaling pathways, but involved impaired virus-mediated membrane fusion. ARB's affinity for membranes may inhibit several aspects of the HCV lifecycle that are membrane-dependent.

  19. Broad spectrum pro-quorum-sensing molecules as inhibitors of virulence in vibrios.

    Directory of Open Access Journals (Sweden)

    Wai-Leung Ng

    Full Text Available Quorum sensing (QS is a bacterial cell-cell communication process that relies on the production and detection of extracellular signal molecules called autoinducers. QS allows bacteria to perform collective activities. Vibrio cholerae, a pathogen that causes an acute disease, uses QS to repress virulence factor production and biofilm formation. Thus, molecules that activate QS in V. cholerae have the potential to control pathogenicity in this globally important bacterium. Using a whole-cell high-throughput screen, we identified eleven molecules that activate V. cholerae QS: eight molecules are receptor agonists and three molecules are antagonists of LuxO, the central NtrC-type response regulator that controls the global V. cholerae QS cascade. The LuxO inhibitors act by an uncompetitive mechanism by binding to the pre-formed LuxO-ATP complex to inhibit ATP hydrolysis. Genetic analyses suggest that the inhibitors bind in close proximity to the Walker B motif. The inhibitors display broad-spectrum capability in activation of QS in Vibrio species that employ LuxO. To the best of our knowledge, these are the first molecules identified that inhibit the ATPase activity of a NtrC-type response regulator. Our discovery supports the idea that exploiting pro-QS molecules is a promising strategy for the development of novel anti-infectives.

  20. A High-Throughput Screen Identifies a New Natural Product with Broad-Spectrum Antibacterial Activity

    Science.gov (United States)

    Ymele-Leki, Patrick; Cao, Shugeng; Sharp, Jared; Lambert, Kathleen G.; McAdam, Alexander J.; Husson, Robert N.; Tamayo, Giselle; Clardy, Jon; Watnick, Paula I.

    2012-01-01

    Due to the inexorable invasion of our hospitals and communities by drug-resistant bacteria, there is a pressing need for novel antibacterial agents. Here we report the development of a sensitive and robust but low-tech and inexpensive high-throughput metabolic screen for novel antibiotics. This screen is based on a colorimetric assay of pH that identifies inhibitors of bacterial sugar fermentation. After validation of the method, we screened over 39,000 crude extracts derived from organisms that grow in the diverse ecosystems of Costa Rica and identified 49 with reproducible antibacterial effects. An extract from an endophytic fungus was further characterized, and this led to the discovery of three novel natural products. One of these, which we named mirandamycin, has broad-spectrum antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Vibrio cholerae, methicillin-resistant Staphylococcus aureus, and Mycobacterium tuberculosis. This demonstrates the power of simple high throughput screens for rapid identification of new antibacterial agents from environmental samples. PMID:22359585

  1. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses.

    Science.gov (United States)

    Sui, Jianhua; Hwang, William C; Perez, Sandra; Wei, Ge; Aird, Daniel; Chen, Li-mei; Santelli, Eugenio; Stec, Boguslaw; Cadwell, Greg; Ali, Maryam; Wan, Hongquan; Murakami, Akikazu; Yammanuru, Anuradha; Han, Thomas; Cox, Nancy J; Bankston, Laurie A; Donis, Ruben O; Liddington, Robert C; Marasco, Wayne A

    2009-03-01

    Influenza virus remains a serious health threat, owing to its ability to evade immune surveillance through rapid genetic drift and reassortment. Here we used a human non-immune antibody phage-display library and the H5 hemagglutinin ectodomain to select ten neutralizing antibodies (nAbs) that were effective against all group 1 influenza viruses tested, including H5N1 'bird flu' and the H1N1 'Spanish flu'. The crystal structure of one such nAb bound to H5 shows that it blocks infection by inserting its heavy chain into a conserved pocket in the stem region, thus preventing membrane fusion. Nine of the nAbs employ the germline gene VH1-69, and all seem to use the same neutralizing mechanism. Our data further suggest that this region is recalcitrant to neutralization escape and that nAb-based immunotherapy is a promising strategy for broad-spectrum protection against seasonal and pandemic influenza viruses.

  2. Broad-spectrum resistance to Bacillus thuringiensis toxins by western corn rootworm (Diabrotica virgifera virgifera).

    Science.gov (United States)

    Jakka, Siva R K; Shrestha, Ram B; Gassmann, Aaron J

    2016-06-14

    The evolution of resistance and cross-resistance threaten the sustainability of genetically engineered crops that produce insecticidal toxins derived from the bacterium Bacillus thuringiensis (Bt). Western corn rootworm, Diabrotica virgifera virgifera LeConte, is a serious pest of maize and has been managed with Bt maize since 2003. We conducted laboratory bioassays with maize hybrids producing Bt toxins Cry3Bb1, mCry3A, eCry3.1Ab, and Cry34/35Ab1, which represent all commercialized Bt toxins for management of western corn rootworm. We tested populations from fields where severe injury to Cry3Bb1 maize was observed, and populations that had never been exposed to Bt maize. Consistent with past studies, bioassays indicated that field populations were resistant to Cry3Bb1 maize and mCry3A maize, and that cross-resistance was present between these two types of Bt maize. Additionally, bioassays revealed resistance to eCry3.1Ab maize and cross-resistance among Cry3Bb1, mCry3A and eCry3.1Ab. However, no resistance or cross-resistance was detected for Cry34/35Ab1 maize. This broad-spectrum resistance illustrates the potential for insect pests to develop resistance rapidly to multiple Bt toxins when structural similarities are present among toxins, and raises concerns about the long-term durability of Bt crops for management of some insect pests.

  3. Growth and characterization of broad spectrum infrared emitting GaInAsP/InP heterostructures

    Science.gov (United States)

    Rakovics, V.; Nádas, J.; Réti, I.; Dücső, Cs.; Battistig, G.

    2017-06-01

    Broad spectrum InGaAsP/InP light emitting heterostructures were grown by low temperature liquid phase epitaxy (LPE). The structure of the LED wafers was investigated by optical transmission measurements, and the layer thicknesses were also measured by electron microscopy. Two quaternary light emitting layers of different composition were built in one device structure in order to broaden the usable wavelength range of the emission spectrum. One of the layers is electrically, whereas the other is optically excited as a result of internal absorption and re-emission of the LED light. As a result of this absorption and re-emission process the modified LED chips have substantially broader emission spectra and higher radiance than the conventional surface emitting multi-wavelength NIR LED structures. The two emission peaks of the spectrum were designed for matching the first and second harmonic wavelength of the fundamental absorption band of C-H bonds. The internal quantum efficiency of the wavelength conversion in this type of LEDs is nearly 100%.

  4. Successful five-item triage for the broad spectrum of mental disorders in pregnancy - A validation study

    NARCIS (Netherlands)

    C. Quispel (Chantal); T.A.J. Schneider (Tom); W.J.G. Hoogendijk (Witte); G.J. Bonsel (Gouke); M.P. Lambregtse-van den Berg (Mijke)

    2015-01-01

    textabstractBackground: Mental disorders are prevalent during pregnancy, affecting 10% of women worldwide. To improve triage of a broad spectrum of mental disorders, we investigated the decision impact validity of: 1) a short set of currently used psychiatric triage items, 2) this set with the

  5. Wild coastline birds as reservoirs of broad-spectrum-β-lactamase-producing Enterobacteriaceae in Miami Beach, Florida.

    Science.gov (United States)

    Poirel, Laurent; Potron, Anaïs; De La Cuesta, Carolina; Cleary, Timothy; Nordmann, Patrice; Munoz-Price, L Silvia

    2012-05-01

    A high rate of broad-spectrum-β-lactamase-producing Escherichia coli isolates was identified from seagull and pelican feces collected in the Miami Beach, Florida, area. The most commonly identified resistance determinants were CMY-2 and CTX-M-15. Those wild birds might be therefore considered vehicles for wide dissemination of multidrug-resistant Enterobacteriaceae in the United States.

  6. Cell-penetrating peptide TP10 shows broad-spectrum activity against both Plasmodium falciparum and Trypanosoma brucei brucei.

    Science.gov (United States)

    Arrighi, Romanico B G; Ebikeme, Charles; Jiang, Yang; Ranford-Cartwright, Lisa; Barrett, Michael P; Langel, Ulo; Faye, Ingrid

    2008-09-01

    Malaria and trypanosomiasis are diseases which afflict millions and for which novel therapies are urgently required. We have tested two well-characterized cell-penetrating peptides (CPPs) for antiparasitic activity. One CPP, designated TP10, has broad-spectrum antiparasitic activity against Plasmodium falciparum, both blood and mosquito stages, and against blood-stage Trypanosoma brucei brucei.

  7. Successful five-item triage for the broad spectrum of mental disorders in pregnancy - A validation study

    NARCIS (Netherlands)

    C. Quispel (Chantal); T.A.J. Schneider (Tom); W.J.G. Hoogendijk (Witte); G.J. Bonsel (Gouke); M.P. Lambregtse-van den Berg (Mijke)

    2015-01-01

    textabstractBackground: Mental disorders are prevalent during pregnancy, affecting 10% of women worldwide. To improve triage of a broad spectrum of mental disorders, we investigated the decision impact validity of: 1) a short set of currently used psychiatric triage items, 2) this set with the inclu

  8. Competitive Interaction Between Phytophthora Infestans Effectors Leads to Increased Aggressiveness on Plants Containing Broad-spectrum Late Blight Resistance

    Science.gov (United States)

    The resistance (R) gene RB confers broad-spectrum resistance to potato late blight and belongs. The RB protein recognizes the presence of members of the Phytophthora infestans effector family IPI-O to elicit resistance. Most isolates of the pathogen contain IPI-O variants that are recognized by R...

  9. Microbiome disruption and recovery in the fish Gambusia affinis following exposure to broad-spectrum antibiotic

    Directory of Open Access Journals (Sweden)

    Carlson JM

    2017-05-01

    Full Text Available Jeanette M Carlson,1 Annie B Leonard,1 Embriette R Hyde,2,3 Joseph F Petrosino,2,3 Todd P Primm1 1Department of Biological Sciences, Sam Houston State University, Huntsville, 2Alkek Center for Metagenomics and Microbiome Research, 3Integrative Molecular and Biomedical Sciences Training Program, Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX, USA Abstract: Antibiotics are a relatively common disturbance to the normal microbiota of humans and agricultural animals, sometimes resulting in severe side effects such as antibiotic-associated enterocolitis. Gambusia affinis was used as a vertebrate model for effects of a broad-spectrum antibiotic, rifampicin, on the skin and gut mucosal microbiomes. The fish were exposed to the antibiotic in the water column for 1 week, and then monitored during recovery. As observed via culture, viable counts from the skin microbiome dropped strongly yet returned to pretreatment levels by 1.6 days and became >70% resistant. The gut microbiome counts dropped and took longer to recover (2.6 days, and became >90% drug resistant. The resistance persisted at ~20% of skin counts in the absence of antibiotic selection for 2 weeks. A community biochemical analysis measuring the presence/absence of 31 activities observed a 39% change in results after 3 days of antibiotic treatment. The antibiotic lowered the skin and gut microbiome community diversity and altered taxonomic composition, observed by 16S rRNA profiling. A 1-week recovery period did not return diversity or composition to pretreatment levels. The genus Myroides dominated both the microbiomes during the treatment, but was not stable and declined in abundance over time during recovery. Rifampicin selected for members of the family Comamonadaceae in the skin but not the gut microbiome. Consistent with other studies, this tractable animal model shows lasting effects on mucosal microbiomes following antibiotic exposure, including

  10. Pyrodiversity and the anthropocene: the role of fire in the broad spectrum revolution.

    Science.gov (United States)

    Bird, Douglas W; Bliege Bird, Rebecca; Codding, Brian F

    2016-05-06

    The Anthropocene colloquially refers to a global regime of human-caused environmental modification of earth systems associated with profound changes in patterns of human mobility, as well as settlement and resource use compared with prior eras. Some have argued that the processes generating the Anthropocene are mainly associated with population growth and technological innovation, and thus began only in the late Holocene under conditions of dense sedentism and industrial agriculture.(1) However, it now seems clear that the roots of the Anthropocene lie in complex processes of intensification that significantly predate transitions to agriculture.(2,3) What intensification is remains less clear. For some it is increasing economic productivity that increases carrying capacity, the drivers of which may be too diverse and too local to generalize.(4,5) For others using Boserup's ideas about agrarian intensification, increasing density in hunter-gatherer populations can produce declines in subsistence efficiency that increase incentives for investing labor to boost yield per unit area, which then elevates Malthusian limits on carrying capacity.(6-8) As Morgan(9) demonstrates in a comprehensive review, the legacy of such Boserupian intensification is alive, well, and controversial in hunter-gatherer archeology. This is a result of its potential for illuminating processes involved in transformations of forager socio-political and economic systems, including those dominated by harvesting more immediate-return resources and high residential mobility as well as those characterized by more delayed-return material economies with reduced residential mobility, a broader spectrum of resources, degrees of storage, and greater social stratification. Here we detail hypotheses about the processes involved in such transitions and explore the way that anthropogenic disturbance of ecosystems, especially the use of landscape fire, could be fundamentally entangled with many broad-spectrum

  11. Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity.

    Directory of Open Access Journals (Sweden)

    Marie-Line Goulet

    Full Text Available The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between cytosolic RIG-I and viral RNA structures that contain short hairpin dsRNA and 5' triphosphate (5'ppp terminal structure. In the present study, an RNA agonist of RIG-I was synthesized in vitro and shown to stimulate RIG-I-dependent antiviral responses at concentrations in the picomolar range. In human lung epithelial A549 cells, 5'pppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, and induction of inflammatory and interferon stimulated genes - hallmarks of a fully functional antiviral response. Evaluation of the magnitude and duration of gene expression by transcriptional profiling identified a robust, sustained and diversified antiviral and inflammatory response characterized by enhanced pathogen recognition and interferon (IFN signaling. Bioinformatics analysis further identified a transcriptional signature uniquely induced by 5'pppRNA, and not by IFNα-2b, that included a constellation of IRF7 and NF-kB target genes capable of mobilizing multiple arms of the innate and adaptive immune response. Treatment of primary PBMCs or lung epithelial A549 cells with 5'pppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 5'pppRNA protected animals from a lethal challenge with H1N1 Influenza, reduced virus titers in mouse lungs and protected animals from virus-induced pneumonia. Strikingly, the RIG-I-specific transcriptional response afforded partial protection from influenza challenge, even in the absence of type I interferon signaling. This systems approach provides transcriptional, biochemical, and in vivo analysis of the antiviral efficacy of 5'pppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents.

  12. Depletion of Cultivatable Gut Microbiota by Broad-Spectrum Antibiotic Pretreatment Worsens Outcome After Murine Stroke

    Science.gov (United States)

    Winek, Katarzyna; Engel, Odilo; Koduah, Priscilla; Heimesaat, Markus M.; Fischer, André; Bereswill, Stefan; Dames, Claudia; Kershaw, Olivia; Gruber, Achim D.; Curato, Caterina; Oyama, Naoki; Meisel, Christian; Meisel, Andreas

    2016-01-01

    Background and Purpose— Antibiotics disturbing microbiota are often used in treatment of poststroke infections. A bidirectional brain–gut microbiota axis was recently suggested as a modulator of nervous system diseases. We hypothesized that gut microbiota may be an important player in the course of stroke. Methods— We investigated the outcome of focal cerebral ischemia in C57BL/6J mice after an 8-week decontamination with quintuple broad-spectrum antibiotic cocktail. These microbiota-depleted animals were subjected to 60 minutes middle cerebral artery occlusion or sham operation. Infarct volume was measured using magnetic resonance imaging, and mice were monitored clinically throughout the whole experiment. At the end point, tissues were preserved for further analysis, comprising histology and immunologic investigations using flow cytometry. Results— We found significantly decreased survival in the middle cerebral artery occlusion microbiota-depleted mice when the antibiotic cocktail was stopped 3 days before surgery (compared with middle cerebral artery occlusion specific pathogen-free and sham-operated microbiota-depleted mice). Moreover, all microbiota-depleted animals in which antibiotic treatment was terminated developed severe acute colitis. This phenotype was rescued by continuous antibiotic treatment or colonization with specific pathogen-free microbiota before surgery. Further, infarct volumes on day one did not differ between any of the experimental groups. Conclusions— Conventional microbiota ensures intestinal protection in the mouse model of experimental stroke and prevents development of acute and severe colitis in microbiota-depleted mice not given antibiotic protection after cerebral ischemia. Our experiments raise the clinically important question as to whether microbial colonization or specific microbiota are crucial for stroke outcome. PMID:27056982

  13. Activities of ceftobiprole, a novel broad-spectrum cephalosporin, against Haemophilus influenzae and Moraxella catarrhalis.

    Science.gov (United States)

    Bogdanovich, Tatiana; Clark, Catherine; Ednie, Lois; Lin, Gengrong; Smith, Kathy; Shapiro, Stuart; Appelbaum, Peter C

    2006-06-01

    Ceftobiprole, a broad-spectrum pyrrolidinone-3-ylidenemethyl cephem currently in phase III clinical trials, had MICs between 0.008 microg/ml and 8.0 microg/ml for 321 clinical isolates of Haemophilus influenzae and between Ceftobiprole MIC(50) and MIC(90) values for H. influenzae were 0.06 microg/ml and 0.25 microg/ml for beta-lactamase-positive strains (n = 262), 0.03 microg/ml and 0.25 microg/ml for beta-lactamase-negative strains (n = 40), and 0.5 microg/ml and 2.0 microg/ml for beta-lactamase-negative ampicillin-resistant strains (n = 19), respectively. Ceftobiprole MIC(50) and MIC(90) values for beta-lactamase-positive M. catarrhalis strains (n = 40) were 0.12 microg/ml and 0.5 microg/ml, respectively, whereas the ceftobiprole MIC range for beta-lactamase-negative M. catarrhalis strains (n = 9) was ceftobiprole, whereas amoxicillin-clavulanate MICs usually were higher than those of ceftobiprole. Azithromycin and telithromycin had unimodal MIC distributions against H. influenzae, with MIC(90) values of azithromycin and telithromycin of 2 microg/ml and 4 microg/ml, respectively. Except for selected quinolone-nonsusceptible H. influenzae strains, moxifloxacin proved highly active, with MIC(90) values of 0.12 microg/ml. Time-kill analyses showed that ceftobiprole, ceftriaxone, cefpodoxime, amoxicillin-clavulanate, azithromycin, telithromycin, and moxifloxacin were bactericidal at 2x MIC by 24 h against all 10 H. influenzae strains surveyed. Only modest increases in MICs were found for H. influenzae or M. catarrhalis clones after 50 serial passages in the presence of subinhibitory concentrations of ceftobiprole, and single-passage selection showed that the selection frequency of H. influenzae or M. catarrhalis clones with elevated ceftobiprole MICs is quite low.

  14. A Broad-Spectrum Integrative Design for Cancer Prevention and Therapy

    Science.gov (United States)

    Block, Keith I.; Gyllenhaal, Charlotte; Lowe, Leroy; Amedei, Amedeo; Amin, A.R.M. Ruhul; Amin, Amr; Aquilano, Katia; Arbiser, Jack; Arreola, Alexandra; Arzumanyan, Alla; Ashraf, S. Salman; Azmi, Asfar S.; Benencia, Fabian; Bhakta, Dipita; Bilsland, Alan; Bishayee, Anupam; Blain, Stacy W.; Block, Penny B.; Boosani, Chandra S.; Carey, Thomas E.; Carnero, Amancio; Carotenuto, Marianeve; Casey, Stephanie C.; Chakrabarti, Mrinmay; Chaturvedi, Rupesh; Chen, Georgia Zhuo; Chen, Helen; Chen, Sophie; Chen, Yi Charlie; Choi, Beom K.; Ciriolo, Maria Rosa; Coley, Helen M.; Collins, Andrew R.; Connell, Marisa; Crawford, Sarah; Curran, Colleen S.; Dabrosin, Charlotta; Damia, Giovanna; Dasgupta, Santanu; DeBerardinis, Ralph J.; Decker, William K.; Dhawan, Punita; Diehl, Anna Mae E.; Dong, Jin-Tang; Dou, Q. Ping; Drew, Janice E.; Elkord, Eyad; El-Rayes, Bassel; Feitelson, Mark A.; Felsher, Dean W.; Ferguson, Lynnette R; Fimognari, Carmela; Firestone, Gary L.; Frezza, Christian; Fujii, Hiromasa; Fuster, Mark M.; Generali, Daniele; Georgakilas, Alexandros G.; Gieseler, Frank; Gilbertson, Michael; Green, Michelle F.; Grue, Brendan; Guha, Gunjan; Halicka, Dorota; Helferich, William G.; Heneberg, Petr; Hentosh, Patricia; Hirschey, Matthew D.; Hofseth, Lorne J.; Holcombe, Randall F.; Honoki, Kanya; Hsu, Hsue-Yin; Huang, Gloria S.; Jensen, Lasse D.; Jiang, Wen G.; Jones, Lee W.; Karpowicz, Phillip A.; Keith, W Nicol; Kerkar, Sid P.; Khan, Gazala N.; Khatami, Mahin; Ko, Young H.; Kucuk, Omer; Kulathinal, Rob J.; Kumar, Nagi B.; Kumara, H.M.C. Shantha; Kwon, Byoung S.; Le, Anne; Lea, Michael A.; Lee, Ho-Young; Lichtor, Terry; Lin, Liang-Tzung; Locasale, Jason W.; Lokeshwar, Bal L.; Longo, Valter D.; Lyssiotis, Costas A.; MacKenzie, Karen L.; Malhotra, Meenakshi; Marino, Maria; Martinez-Chantar, Maria L.; Matheu, Ander; Maxwell, Christopher; McDonnell, Eoin; Meeker, Alan K.; Mehrmohamadi, Mahya; Mehta, Kapil; Michelotti, Gregory A.; Mohammad, Ramzi M.; Mohammed, Sulma I.; Morre, D. James; Muqbil, Irfana; Muralidhar, Vinayak; Murphy, Michael P.; Nagaraju, Ganji Purnachandra; Nahta, Rita; Niccolai, Elena; Nowsheen, Somaira; Panis, Carolina; Pantano, Francesco; Parslow, Virginia R.; Pawelec, Graham; Pedersen, Peter L.; Poore, Brad; Poudyal, Deepak; Prakash, Satya; Prince, Mark; Raffaghello, Lizzia; Rathmell, Jeffrey C.; Rathmell, W. Kimryn; Ray, Swapan K.; Reichrath, Jörg; Rezazadeh, Sarallah; Ribatti, Domenico; Ricciardiello, Luigi; Robey, R. Brooks; Rodier, Francis; Rupasinghe, H.P. Vasantha; Russo, Gian Luigi; Ryan, Elizabeth P.; Samadi, Abbas K.; Sanchez-Garcia, Isidro; Sanders, Andrew J.; Santini, Daniele; Sarkar, Malancha; Sasada, Tetsuro; Saxena, Neeraj K.; Shackelford, Rodney E; Sharma, Dipali; Shin, Dong M.; Sidransky, David; Siegelin, Markus David; Signori, Emanuela; Singh, Neetu; Sivanand, Sharanya; Sliva, Daniel; Smythe, Carl; Spagnuolo, Carmela; Stafforini, Diana M.; Stagg, John; Subbarayan, Pochi R.; Sundin, Tabetha; Talib, Wamidh H.; Thompson, Sarah K.; Tran, Phuoc T.; Ungefroren, Hendrik; Vander Heiden, Matthew G.; Venkateswaran, Vasundara; Vinay, Dass S.; Vlachostergios, Panagiotis J.; Wang, Zongwei; Wellen, Kathryn E.; Whelan, Richard L.; Yang, Eddy S.; Yang, Huanjie; Yang, Xujuan; Yaswen, Paul; Yedjou, Clement; Yin, Xin; Zhu, Jiyue; Zollo, Massimo

    2016-01-01

    Targeted therapies and the consequent adoption of “personalized” oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity “broad-spectrum” therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested; many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to help us address disease relapse, which is a

  15. Expression of mouse beta defensin 2 in Escherichia coli and its broad-spectrum antimicrobial activity

    Directory of Open Access Journals (Sweden)

    Tianxiang Gong

    2011-09-01

    Full Text Available Mature mouse beta defensin 2 (mBD2 is a small cationic peptide with antimicrobial activity. Here we established a prokaryotic expression vector containing the cDNA of mature mBD2 fused with thioredoxin (TrxA, pET32a-mBD2. The vector was transformed into Escherichia Coli (E. coli Rosseta-gami (2 for expression fusion protein. Under the optimization of fermentation parameters: induce with 0.6 mM isopropylthiogalactoside (IPTG at 34ºC in 2×YT medium and harvest at 6 h postinduction, fusion protein TrxA-mBD2 was high expressed in the soluble fraction (>95%. After cleaved fusion protein by enterokinase, soluble mature mBD2 was achieved 6 mg/L with a volumetric productivity. Purified recombinant mBD2 demonstrated clear broad-spectrum antimicrobial activity for fungi, bacteria and virus. The MIC of antibacterial activity of against Staphylococcus aureus was 50 µg/ml. The MIC of against Candida albicans (C. albicans and Cryptococcus neoformans (C. neoformans was 12.5µg/ml and 25µg/ml, respectively. Also, the antimicrobial activity of mBD2 was effected by NaCl concentration. Additionally, mBD2 showed antiviral activity against influenza A virus (IAV, the protective rate for Madin-Darby canine kidney cells (MDCK was 93.86% at the mBD2 concentration of 100 µg/ml. These works might provide a foundation for the following research on the mBD2 as therapeutic agent for medical microbes.

  16. Manganese Oxide Nanoarchitectures as Broad-Spectrum Sorbents for Toxic Gases.

    Science.gov (United States)

    Long, Jeffrey W; Wallace, Jean M; Peterson, Gregory W; Huynh, Kim

    2016-01-20

    We demonstrate that sol-gel-derived manganese oxide (MnOx) nanoarchitectures exhibit broad-spectrum filtration activity for three chemically diverse toxic gases: NH3, SO2, and H2S. Manganese oxides are synthesized via the reaction of NaMnO4 and fumaric acid to form monolithic gels of disordered, mixed-valent Na-MnOx; incorporated Na(+) is readily exchanged for H(+) by subsequent acid rinsing to form a more crystalline H-MnOx phase. For both Na-MnOx and H-MnOx forms, controlled pore-fluid removal yields either densified, yet still mesoporous, xerogels or low-density aerogels (prepared by drying from supercritical CO2). The performance of these MnOx nanoarchitectures as filtration media is assessed using dynamic-challenge microbreakthrough protocols. We observe technologically relevant sorption capacities under both dry conditions and wet (80% relative humidity) for each of the three toxic industrial chemicals investigated. The Na-MnOx xerogels and aerogels provide optimal performance with the aerogel exhibiting maximum sorption capacities of 39, 200, and 680 mg g(-1) for NH3, SO2, and H2S, respectively. Postbreakthrough characterization using X-ray photoelectron spectroscopy (XPS) and diffuse-reflectance infrared Fourier transform spectroscopy (DRIFTS) confirms that NH3 is captured and partially protonated within the MnOx structure, while SO2 undergoes oxidation by the redox-active oxide to form adsorbed sulfate at the MnOx surface. Hydrogen sulfide is also oxidized to form a combination of sulfate and sulfur/polysulfide products, concomitant with a decrease in the average Mn oxidation state from 3.43 to 2.94 and generation of a MnOOH phase.

  17. Proteasome Accessory Factor C (pafC) Is a novel gene Involved in Mycobacterium Intrinsic Resistance to broad-spectrum antibiotics--Fluoroquinolones

    National Research Council Canada - National Science Library

    Li, Qiming; Xie, Longxiang; Long, Quanxin; Mao, Jinxiao; Li, Hui; Zhou, Mingliang; Xie, Jianping

    2015-01-01

    .... Fluoroquinolones are potent and widely prescribed broad-spectrum antibiotics. Bacterial protein degradation pathways represent novel druggable target for the development of new classes of antibiotics...

  18. A mechanistic paradigm for broad-spectrum antivirals that target virus-cell fusion.

    Directory of Open Access Journals (Sweden)

    Frederic Vigant

    .01 delayed the time to death in a murine lethal challenge model of Rift Valley Fever Virus (RVFV. The viral membrane may be a viable target for broad-spectrum antivirals that target virus-cell fusion.

  19. Integrated DNA walking system to characterize a broad spectrum of GMOs in food/feed matrices.

    Science.gov (United States)

    Fraiture, Marie-Alice; Herman, Philippe; Lefèvre, Loic; Taverniers, Isabel; De Loose, Marc; Deforce, Dieter; Roosens, Nancy H

    2015-08-14

    In order to provide a system fully integrated with qPCR screening, usually used in GMO routine analysis, as well as being able to detect, characterize and identify a broad spectrum of GMOs in food/feed matrices, two bidirectional DNA walking methods targeting p35S or tNOS, the most common transgenic elements found in GM crops, were developed. These newly developed DNA walking methods are completing the previously implemented DNA walking method targeting the t35S pCAMBIA element. Food/feed matrices containing transgenic crops (Bt rice or MON863 maize) were analysed using the integrated DNA walking system. First, the newly developed DNA walking methods, anchored on the sequences used for the p35S or tNOS qPCR screening, were tested on Bt rice that contains these two transgenic elements. Second, the methods were assessed on a maize sample containing a low amount of the GM MON863 event, representing a more complex matrix in terms of genome size and sensitivity. Finally, to illustrate its applicability in GMO routine analysis by enforcement laboratories, the entire workflow of the integrated strategy, including qPCR screening to detect the potential presence of GMOs and the subsequent DNA walking methods to characterize and identify the detected GMOs, was applied on a GeMMA Scheme Proficiency Test matrix. Via the characterization of the transgene flanking region between the transgenic cassette and the plant genome as well as of a part of the transgenic cassette, the presence of GMOs was properly confirmed or infirmed in all tested samples. Due to their simple procedure and their short time-frame to get results, the developed DNA walking methods proposed here can be easily implemented in GMO routine analysis by the enforcement laboratories. In providing crucial information about the transgene flanking regions and/or the transgenic cassettes, this DNA walking strategy is a key molecular tool to prove the presence of GMOs in any given food/feed matrix.

  20. Pharmacy sales data versus ward stock accounting for the surveillance of broad-spectrum antibiotic use in hospitals

    Directory of Open Access Journals (Sweden)

    Haug Jon B

    2011-12-01

    Full Text Available Abstract Background Antibiotic consumption in hospitals is commonly measured using the accumulated amount of drugs delivered from the pharmacy to ward held stocks. The reliability of this method, particularly the impact of the length of the registration periods, has not been evaluated and such evaluation was aim of the study. Methods During 26 weeks, we performed a weekly ward stock count of use of broad-spectrum antibiotics - that is second- and third-generation cephalosporins, carbapenems, and quinolones - in five hospital wards and compared the data with corresponding pharmacy sales figures during the same period. Defined daily doses (DDDs for antibiotics were used as measurement units (WHO ATC/DDD classification. Consumption figures obtained with the two methods for different registration intervals were compared by use of intraclass correlation analysis and Bland-Altman statistics. Results Broad-spectrum antibiotics accounted for a quarter to one-fifth of all systemic antibiotics (ATC group J01 used in the hospital and varied between wards, from 12.8 DDDs per 100 bed days in a urological ward to 24.5 DDDs in a pulmonary diseases ward. For the entire study period of 26 weeks, the pharmacy and ward defined daily doses figures for all broad-spectrum antibiotics differed only by 0.2%; however, for single wards deviations varied from -4.3% to 6.9%. The intraclass correlation coefficient, pharmacy versus ward data, increased from 0.78 to 0.94 for parenteral broad-spectrum antibiotics with increasing registration periods (1-4 weeks, whereas the corresponding figures for oral broad-spectrum antibiotics (ciprofloxacin were from 0.46 to 0.74. For all broad-spectrum antibiotics and for parenteral antibiotics, limits of agreement between the two methods showed, according to Bland-Altman statistics, a deviation of ± 5% or less from average mean DDDs at 3- and 4-weeks registration intervals. Corresponding deviation for oral antibiotics was ± 21% at a 4

  1. Ceftobiprole: a review of a broad-spectrum and anti-MRSA cephalosporin.

    Science.gov (United States)

    Zhanel, George G; Lam, Ashley; Schweizer, Frank; Thomson, Kristjan; Walkty, Andrew; Rubinstein, Ethan; Gin, Alfred S; Hoban, Daryl J; Noreddin, Ayman M; Karlowsky, James A

    2008-01-01

    Ceftobiprole, an investigational cephalosporin, is currently in phase III clinical development. Ceftobiprole is a broad-spectrum cephalosporin with demonstrated in vitro activity against Gram-positive cocci, including meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-resistant S. epidermidis, penicillin-resistant S. pneumoniae, Enterococcus faecalis, Gram-negative bacilli including AmpC-producing Escherichia coli and Pseudomonas aeruginosa, but excluding extended-spectrum beta-lactamase-producing strains. Like cefotaxime, ceftriaxone, ceftazidime, and cefepime, ceftobiprole demonstrates limited activity against anaerobes such as Bacteroides fragilis and non-fragilis Bacteroides spp. In single-step and serial passage in vitro resistance development studies, ceftobiprole demonstrated a low propensity to select for resistant subpopulations. Ceftobiprole, like cefepime, is a weak inducer and a poor substrate for AmpC beta-lactamases.Ceftobiprole medocaril, the prodrug of ceftobiprole, is converted by plasma esterases to ceftobiprole in ceftobiprole observed at the end of a single 30-minute infusion were 35.5 mug/mL for a 500-mg dose and 59.6 mug/mL for a 750-mg dose. The volume of distribution of ceftobiprole is 0.26 L/kg ( approximately 18 L), protein binding is 16%, and its serum half-life is approximately 3.5 hours. Ceftobiprole is renally excreted ( approximately 70% in the active form) and systemic clearance correlates with creatinine clearance, meaning that dosage adjustment is required in patients with renal dysfunction. Ceftobiprole has a modest post-antibiotic effect (PAE) of approximately 0.5 hours for MRSA and a longer PAE of approximately 2 hours for penicillin-resistant pneumococci. Ceftobiprole, when administered intravenously at 500 mg once every 8 hours (2-hour infusion), has a >90% probability of achieving f T(>MIC) (free drug concentration exceeds the minimum inhibitory concentration [MIC]) for 40% and 60%, respectively, of the dosing

  2. AN OVERVIEW OF AZOLE ANTIFUNGALS

    Directory of Open Access Journals (Sweden)

    Pratibha Shivaji Gavarkar*, Rahul Shivaji Adnaik, and Shrinivas Krishna Mohite

    2013-11-01

    Full Text Available Fungal infections in critically ill or immunosuppressed patients were increasing in incidence in the human population over the last 1-2 decades. There were few advances in antifungal therapy and, until recently, there were few choices from which to select a treatment for systemic mycoses. However, in the past decade, there have been several developments in this area. Antifungal agents are sufficiently diverse in activity, toxicity, and drug interaction potential. Azoles are synthetic and semi-synthetic compounds. They have a broad spectrum of activity. Triazole antifungals are active to treat an array of fungal pathogens, whereas imidazoles are used almost exclusively in the treatment of superficial mycoses and vaginal candidiasis. Despite the advances, serious fungal infections remain difficult to treat, and resistance to the available drugs is emerging. Use of the currently available azoles in combination with other antifungal agents with different mechanisms of action is likely to provide enhanced efficacy. The present review aims to explore the pharmacology, pharmacokinetics, spectrum of activity, safety, toxicity and potential for drug–drug interactions of the azole antifungal agents.

  3. NBS Proifling Identiifes Potential Novel Locus from Solanum demissum That Confers Broad-Spectrum Resistance to Phytophthora infestans

    Institute of Scientific and Technical Information of China (English)

    ZHANG Kun; XU Jian-fei; DUAN Shao-guang; PANG Wan-fu; BIAN Chun-song; LIU Jie; JIN Li-ping

    2014-01-01

    Potato late blight, caused by the oomycete pathogen Phytophthora infestans, is the most serious disease of potato worldwide. The adoption of varieties with resistance genes, especially broad-spectrum resistance genes, is the most efifcient approach to control late blight. Solanum demissum is a well-known wild potato species from which 11 race-speciifc resistance genes have been identiifed, however, no broad-spectrum resistance genes like RB have been reported in this species. Here, we report a novel reisistance locus from S. demissum that potentially confer broad-spectrum resistance to late blight. A small segregating population of S. demissum were assessed for resistance to aggressive P. infestans isolates (race 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11). This coupled with nucleotide binding site (NBS) proifling analyses, led to the identiifcation of three fragments that linked to the potential candidate resistance gene(s). Cloning and sequence analysis of these fragments suggested that the identiifed resistance gene locus is located in the region containing R2 resistance gene at chromosome 4. Based on the sequences of the cloned fragments, a co-segregating sequence characterized ampliifed region (SCAR) marker, RDSP, was developed. The newly identiifed marker RDSP will be useful for marker assisted breeding and further cloning of this potential resistance gene locus.

  4. Targeting Class A and C Serine β-Lactamases with a Broad-Spectrum Boronic Acid Derivative

    Science.gov (United States)

    2015-01-01

    Production of β-lactamases (BLs) is the most widespread resistance mechanism adopted by bacteria to fight β-lactam antibiotics. The substrate spectrum of BLs has become increasingly broad, posing a serious health problem. Thus, there is an urgent need for novel BL inhibitors. Boronic acid transition-state analogues are able to reverse the resistance conferred by class A and C BLs. We describe a boronic acid analogue possessing interesting and potent broad-spectrum activity vs class A and C serine-based BLs. Starting from benzo(b)thiophene-2-boronic acid (BZBTH2B), a nanomolar non-β-lactam inhibitor of AmpC that can potentiate the activity of a third-generation cephalosporin against AmpC-producing resistant bacteria, we designed a novel broad-spectrum nanomolar inhibitor of class A and C BLs. Structure-based drug design (SBDD), synthesis, enzymology data, and X-ray crystallography results are discussed. We clarified the inhibitor binding geometry responsible for broad-spectrum activity vs serine-active BLs using double mutant thermodynamic cycle studies. PMID:24882105

  5. Production and characterization of antifungal compounds produced by Lactobacillus plantarum IMAU10014.

    Directory of Open Access Journals (Sweden)

    HaiKuan Wang

    Full Text Available Lactobacillus plantarum IMAU10014 was isolated from koumiss that produces a broad spectrum of antifungal compounds, all of which were active against plant pathogenic fungi in an agar plate assay. Two major antifungal compounds were extracted from the cell-free supernatant broth of L. plantarum IMAU10014. 3-phenyllactic acid and Benzeneacetic acid, 2-propenyl ester were carried out by HPLC, LC-MS, GC-MS, NMR analysis. It is the first report that lactic acid bacteria produce antifungal Benzeneacetic acid, 2-propenyl ester. Of these, the antifungal products also have a broad spectrum of antifungal activity, namely against Botrytis cinerea, Glomerella cingulate, Phytophthora drechsleri Tucker, Penicillium citrinum, Penicillium digitatum and Fusarium oxysporum, which was identified by the overlay and well-diffusion assay. F. oxysporum, P. citrinum and P. drechsleri Tucker were the most sensitive among molds.

  6. Pinellia ternata agglutinin expression in chloroplasts confers broad spectrum resistance against aphid, whitefly, Lepidopteran insects, bacterial and viral pathogens.

    Science.gov (United States)

    Jin, Shuangxia; Zhang, Xianlong; Daniell, Henry

    2012-04-01

    Broad spectrum protection against different insects and pathogens requires multigene engineering. However, such broad spectrum protection against biotic stress is provided by a single protein in some medicinal plants. Therefore, tobacco chloroplasts were transformed with the agglutinin gene from Pinellia ternata (pta), a widely cultivated Chinese medicinal herb. Pinellia ternata agglutinin (PTA) was expressed up to 9.2% of total soluble protein in mature leaves. Purified PTA showed similar hemagglutination activity as snowdrop lectin. Artificial diet with purified PTA from transplastomic plants showed marked and broad insecticidal activity. In planta bioassays conducted with T0 or T1 generation PTA lines showed that the growth of aphid Myzus persicae (Sulzer) was reduced by 89%-92% when compared with untransformed (UT) plants. Similarly, the larval survival and total population of whitefly (Bemisia tabaci) on transplastomic lines were reduced by 91%-93% when compared with UT plants. This is indeed the first report of lectin controlling whitefly infestation. When transplastomic PTA leaves were fed to corn earworm (Helicoverpa zea), tobacco budworm (Heliothis virescens) or the beet armyworm (spodoptera exigua), 100% mortality was observed against all these three insects. In planta bioassays revealed Erwinia population to be 10,000-fold higher in control than in PTA lines. Similar results were observed with tobacco mosaic virus (TMV) challenge. Therefore, broad spectrum resistance to homopteran (sap-sucking), Lepidopteran insects as well as anti-bacterial or anti-viral activity observed in PTA lines provides a new option to engineer protection against biotic stress by hyper-expression of an unique protein that is naturally present in a medicinal plant.

  7. Proteinaceous molecules mediating Bifidobacterium-host interactions

    Directory of Open Access Journals (Sweden)

    Lorena Ruiz

    2016-08-01

    Full Text Available Bifidobacteria are commensal microoganisms found in the gastrointestinal tract.Several strains have been attributed beneficial traits at local and systemic levels, through pathogen exclusion or immune modulation, among other benefits. This has promoted a growing industrial and scientific interest in bifidobacteria as probiotic supplements. However, the molecular mechanisms mediating this cross-talk with the human host remain unknown. High-throughput technologies, from functional genomics to transcriptomics, proteomics and interactomics coupled to the development of both in vitro and in vivo models to study the dynamics of the intestinal microbiota and their effects on host cells, have eased the identification of key molecules in these interactions. Numerous secreted or surface-associated proteins or peptides have been identified as potential mediators of bifidobacteria-host interactions and molecular cross-talk, directly participating in sensing environmental factors, promoting intestinal colonization or mediating a dialogue with mucosa-associated immune cells. On the other hand, bifidobacteria induce the production of proteins in the intestine, by epithelial or immune cells, and other gut bacteria, which are key elements in orchestrating interactions among bifidobacteria, gut microbiota and host cells. This review aims to give a comprehensive overview on proteinaceous molecules described and characterized to date, as mediators of the dynamic interplay between bifidobacteria and the human host, providing a framework to identify knowledge gaps and future research needs.

  8. Broad-spectrum acquired resistance in barley induced by the Pseudomonas pathosystem shares transcriptional components with Arabidopsis systemic acquired resistance.

    Science.gov (United States)

    Colebrook, E H; Creissen, G; McGrann, G R D; Dreos, R; Lamb, C; Boyd, L A

    2012-05-01

    Inducible resistance responses play a central role in the defense of plants against pathogen attack. Acquired resistance (AR) is induced alongside defense toward primary attack, providing broad-spectrum protection against subsequent pathogen challenge. The localization and molecular basis of AR in cereals is poorly understood, in contrast with the well-characterized systemic acquired resistance (SAR) response in Arabidopsis. Here, we use Pseudomonas syringae as a biological inducer of AR in barley, providing a clear frame of reference to the Arabidopsis-P. syringae pathosystem. Inoculation of barley leaf tissue with the nonadapted P. syringae pv. tomato avrRpm1 (PstavrRpm1) induced an active local defense response. Furthermore, inoculation of barley with PstavrRpm1 resulted in the induction of broad-spectrum AR at a distance from the local lesion, "adjacent" AR, effective against compatible isolates of P. syringae and Magnaporthe oryzae. Global transcriptional profiling of this adjacent AR revealed similarities with the transcriptional profile of SAR in Arabidopsis, as well as transcripts previously associated with chemically induced AR in cereals, suggesting that AR in barley and SAR in Arabidopsis may be mediated by analogous pathways.

  9. Design of a photostabilizer having built-in antioxidant functionality and its utility in obtaining broad-spectrum sunscreen formulations.

    Science.gov (United States)

    Chaudhuri, Ratan K; Lascu, Zoia; Puccetti, Germain; Deshpande, Anant A; Paknikar, Sashikumar K

    2006-01-01

    Di-2,2'-diethylhexyl-3,5-dimethoxy-4-hydroxy-benzylidenemalonate (INCI name diethylhexyl syringylidene malonate, DESM), the target photostabilizer, was synthesized in one step by condensation of 3,5-dimethoxy-4-hydroxy benzaldehyde (Syringaldehyde) with di-2,2'-diethylhexyl malonate. Photostability data in sunscreen formulations showed that DESM is photostable and improves the photostability of avobenzone significantly when compared to control (without a photostabilizer). Photostable broad-spectrum sunscreen formulations with high SPF (>30) have been achieved by combining avobenzone, DESM and UV-B sunscreens, such as homosalate, octisalate or other UV-B sunscreens. It seems that (a) triplet-state energy transfer from avobenzone to DESM and (b) scavenging of reactive species are responsible for the observed stabilization of avobenzone. In vitro study of the two formulations containing DESM clearly showed critical wavelength of well over 370 nm and can thus be categorized as broad-spectrum sunscreens. DESM does not have any contribution to in vivo SPF; instead it boosts SPF by about 5 units in high-SPF products. DESM was found to be an excellent singlet-oxygen quencher, thereby reducing photodegradation of avobenzone caused by singlet oxygen. In short, the multiplicity of effects and formulation benefits seen with DESM makes it an ideal choice as a unique antioxidant photostabilizer for a variety of cosmetic products targeting young and mature skin alike.

  10. Development of a broad spectrum polymer-released antimicrobial coating for the prevention of resistant strain bacterial infections.

    Science.gov (United States)

    Sinclair, K D; Pham, T X; Farnsworth, R W; Williams, D L; Loc-Carrillo, C; Horne, L A; Ingebretsen, S H; Bloebaum, R D

    2012-10-01

    More than 400,000 primary hip and knee replacement surgeries are performed each year in the United States. From these procedures, approximately 0.5-3% will become infected and when considering revision surgeries, this rate has been found to increase significantly. Antibiotic-resistant bacterial infections are a growing problem in patient care. This in vitro research investigated the antimicrobial potential of the polymer released, broad spectrum, Cationic Steroidal Antimicrobial-13 (CSA-13) for challenges against 5 × 10(8) colony forming units (CFU) of methicillin-resistant Staphylococcus aureus (MRSA). It was hypothesized that a weight-to-weight (w/w) concentration of 18% CSA-13 in silicone would exhibit potent bactericidal potential when used as a controlled release device coating. When incorporated into a polymeric device coating, the 18% (w/w) broad-spectrum polymer released CSA-13 antimicrobial eliminated 5 × 10(8) CFU of MRSA within 8 h. In the future, these results will be utilized to develop a sheep model to assess CSA-13 for the prevention of perioperative device-related infections in vivo.

  11. A novel Pro197Glu substitution in acetolactate synthase (ALS) confers broad-spectrum resistance across ALS inhibitors.

    Science.gov (United States)

    Liu, Weitang; Yuan, Guohui; Du, Long; Guo, Wenlei; Li, Lingxu; Bi, Yaling; Wang, Jinxin

    2015-01-01

    Water chickweed (Myosoton aquaticum L.), a competitive broadleaf weed, is widespread in wheat fields in China. Tribenuron and pyroxsulam failed to control water chickweed in the same field in Qiaotian Village in 2011 and 2012, respectively. An initial tribenuron resistance confirmation test identified a resistant population (AH02). ALS gene sequencing revealed a previously unreported substitution of Glu for Pro at amino acid position 197 in resistant individuals. A purified subpopulation (WRR04) that was individually homozygous for the Pro197Glu substitution was generated and characterized in terms of its response to different classes of ALS inhibitors. A whole-plant experiment showed that the WRR04 population exhibited broad-spectrum resistance to tribenuron (SU, 318-fold), pyrithiobac sodium (PTB, > 197-fold), pyroxsulam (TP, 81-fold), florasulam (TP, > 36-fold) and imazethapyr (IMI, 11-fold). An in vitro ALS assay confirmed that the ALS from WRR04 showed high resistance to all the tested ALS inhibitors. These results established that the Pro197Glu substitution endows broad-spectrum resistance across ALS inhibitors in water chickweed. In addition, molecular markers were developed to rapidly identify the Pro197Glu mutation.

  12. Broad-Spectrum Inhibition of Respiratory Virus Infection by MicroRNA Mimics Targeting p38 MAPK Signaling.

    Science.gov (United States)

    McCaskill, Jana L; Ressel, Sarah; Alber, Andreas; Redford, Jane; Power, Ultan F; Schwarze, Jürgen; Dutia, Bernadette M; Buck, Amy H

    2017-06-16

    The majority of antiviral therapeutics target conserved viral proteins, however, this approach confers selective pressure on the virus and increases the probability of antiviral drug resistance. An alternative therapeutic strategy is to target the host-encoded factors that are required for virus infection, thus minimizing the opportunity for viral mutations that escape drug activity. MicroRNAs (miRNAs) are small noncoding RNAs that play diverse roles in normal and disease biology, and they generally operate through the post-transcriptional regulation of mRNA targets. We have previously identified cellular miRNAs that have antiviral activity against a broad range of herpesvirus infections, and here we extend the antiviral profile of a number of these miRNAs against influenza and respiratory syncytial virus. From these screening experiments, we identified broad-spectrum antiviral miRNAs that caused >75% viral suppression in all strains tested, and we examined their mechanism of action using reverse-phase protein array analysis. Targets of lead candidates, miR-124, miR-24, and miR-744, were identified within the p38 mitogen-activated protein kinase (MAPK) signaling pathway, and this work identified MAPK-activated protein kinase 2 as a broad-spectrum antiviral target required for both influenza and respiratory syncytial virus (RSV) infection. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  13. A multidisciplinary antimicrobial stewardship programme safely decreases the duration of broad-spectrum antibiotic prescription in Singaporean adult renal patients.

    Science.gov (United States)

    Cai, Yiying; Shek, Pui Ying; Teo, Isabelle; Tang, Sarah S L; Lee, Winnie; Liew, Yi Xin; Chlebicki, Piotr; Kwa, Andrea L

    2016-01-01

    Patients with chronic kidney disease have increased risk of infections. Thus, physicians may favour prolonged broad-spectrum antibiotic use. Studies focused on antimicrobial stewardship programmes (ASPs) in renal patients are currently lacking. Here we describe the role of a multidisciplinary ASP and the impact of ASP interventions in renal patients. A multidisciplinary ASP was initiated at a tertiary hospital in Singapore. Patients prescribed broad-spectrum parenteral antibiotics were identified daily and were subjected to prospective review with immediate concurrent feedback. ASP data from January 2010 to December 2011 were analysed for all renal patients. Outcome measures included the duration and appropriateness of antibiotics, intervention acceptance rates, cost savings and safety outcomes. A total of 2084 antibiotic courses were reviewed, of which 24% were inappropriate, with meropenem most commonly prescribed inappropriately (31.0%). The commonest reasons for inappropriate use were wrong choice (51.0%) and wrong duration (21.4%). In total, 634 recommendations were made, with high acceptance rates (73.3%). Recommendations to discontinue antibiotics (33.4%) and to optimise doses (17.2%) comprised the bulk of ASP work. A mean reduction of -1.28 days of antibiotic use was observed among patients with interventions accepted versus those rejected (Pantibiotic use without compromising safety in renal patients. Continued effort is needed to produce a long-term impact on antibiotic prescription and resistance.

  14. Occurrence of bacteria producing broad-spectrum beta-lactamases and qnr genes in hospital and urban wastewater samples.

    Science.gov (United States)

    Röderová, Magdaléna; Sedláková, Miroslava Htoutou; Pudová, Vendula; Hricová, Kristýna; Silová, Romana; Imwensi, Peter Eghonghon Odion; Bardoň, Jan; Kolář, Milan

    2016-04-01

    The aims were to investigate the level of antibiotic-resistant bacteria in hospital and urban wastewater and to determine the similarity of isolates obtained from wastewater and hospitalized patients. Wastewater samples were collected in September 2013 and 2014. After identification using MALDI-TOF MS, beta-lactamase production was determined by relevant phenotypic tests. Genes responsible for the production of single beta-lactamase groups and Qnr proteins were established. The epidemiological relationship of the isolates from wastewater and hospitalized patients was determined by PFGE. A total of 51 isolates of enterobacteria were obtained. Overall, 45.1% of them produced broad-spectrum beta-lactamases. Genes encoding TEM, SHV, CTX-M, CIT, DHA and EBC types of enzymes and Qnr proteins were detected. No broad-spectrum beta-lactamase production was confirmed in the urban wastewater treatment plant. The most important finding was the detection of two identical isolates of K. pneumoniae in 2013, one from a patient's urinary catheter and the other from a wastewater sample.

  15. Potential Broad Spectrum Inhibitors of the Coronavirus 3CLpro: A Virtual Screening and Structure-Based Drug Design Study.

    Science.gov (United States)

    Berry, Michael; Fielding, Burtram C; Gamieldien, Junaid

    2015-12-15

    Human coronaviruses represent a significant disease burden; however, there is currently no antiviral strategy to combat infection. The outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) less than 10 years later demonstrates the potential of coronaviruses to cross species boundaries and further highlights the importance of identifying novel lead compounds with broad spectrum activity. The coronavirus 3CL(pro) provides a highly validated drug target and as there is a high degree of sequence homology and conservation in main chain architecture the design of broad spectrum inhibitors is viable. The ZINC drugs-now library was screened in a consensus high-throughput pharmacophore modeling and molecular docking approach by Vina, Glide, GOLD and MM-GBSA. Molecular dynamics further confirmed results obtained from structure-based techniques. A highly defined hit-list of 19 compounds was identified by the structure-based drug design methodologies. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds is bioactive is excellent. Additionally, the compounds segregate into 15 significantly dissimilar (p < 0.05) clusters based on shape and features, which represent valuable scaffolds that can be used as a basis for future anti-coronaviral inhibitor discovery experiments. Importantly though, the enriched subset of 19 compounds identified from the larger library has to be validated experimentally.

  16. Novel engineered cationic antimicrobial peptides display broad-spectrum activity against Francisella tularensis, Yersinia pestis and Burkholderia pseudomallei.

    Science.gov (United States)

    Abdelbaqi, Suha; Deslouches, Berthony; Steckbeck, Jonathan; Montelaro, Ronald; Reed, Douglas S

    2016-02-01

    Broad-spectrum antimicrobials are needed to effectively treat patients infected in the event of a pandemic or intentional release of a pathogen prior to confirmation of the pathogen's identity. Engineered cationic antimicrobial peptides (eCAPs) display activity against a number of bacterial pathogens including multi-drug-resistant strains. Two lead eCAPs, WLBU2 and WR12, were compared with human cathelicidin (LL-37) against three highly pathogenic bacteria: Francisella tularensis, Yersinia pestis and Burkholderia pseudomallei. Both WLBU2 and WR12 demonstrated bactericidal activity greater than that of LL-37, particularly against F. tularensis and Y. pestis. Only WLBU2 had bactericidal activity against B. pseudomallei. WLBU2, WR12 and LL-37 were all able to inhibit the growth of the three bacteria in vitro. Because these bacteria can be facultative intracellular pathogens, preferentially infecting macrophages and dendritic cells, we evaluated the activity of WLBU2 against F. tularensis in an ex vivo infection model with J774 cells, a mouse macrophage cell line. In that model WLBU2 was able to achieve greater than 50% killing of F. tularensis at a concentration of 12.5 μM. These data show the therapeutic potential of eCAPs, particularly WLBU2, as a broad-spectrum antimicrobial for treating highly pathogenic bacterial infections.

  17. Advances in synthetic approach to and antifungal activity of triazoles

    Directory of Open Access Journals (Sweden)

    Pramod Kumar Sharma

    2011-05-01

    Full Text Available Several five membered ring systems, e.g., triazole, oxadiazole dithiazole and thiadiazole with three heteroatoms at symmetrical or asymmetrical positions have been studied because of their interesting pharmacological properties. In this article our emphasis is on synthetic development and pharmacological activity of the triazole moiety which exhibit a broad spectrum of pharmacological activity such as antifungal, antibacterial, anti-inflammatory and anticancer etc. Triazoles have increased our ability to treat many fungal infections, for example, candidiasis, cryptococcal meningitis, aspergillosis etc. However, mortality due to these infections even with antifungal therapy is still unacceptably high. Therefore, the development of new antifungal agents targeting specific fungal structures or functions is being actively pursued. Rapid developments in molecular mycology have led to a concentrated search for more target antifungals. Although we are entering a new era of antifungal therapy in which we will continue to be challenged by systemic fungal diseases, the options for treatment will have greatly expanded.

  18. Fabrication of submicron proteinaceous structures by direct laser writing

    Energy Technology Data Exchange (ETDEWEB)

    Serien, Daniela [Center for International Research on Integrative Biomedical Systems, Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, 153-8505 Tokyo (Japan); Takeuchi, Shoji, E-mail: takeuchi@iis.u-tokyo.ac.jp [Center for International Research on Integrative Biomedical Systems, Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, 153-8505 Tokyo (Japan); ERATO Takeuchi Biohybrid Innovation Project, Japan Science and Technology Agency, 4-6-1 Komaba, Meguro-ku, 153-8505 Tokyo (Japan)

    2015-07-06

    In this paper, we provide a characterization of truly free-standing proteinaceous structures with submicron feature sizes depending on the fabrication conditions by model-based analysis. Protein cross-linking of bovine serum albumin is performed by direct laser writing and two-photon excitation of flavin adenine dinucleotide. We analyze the obtainable fabrication resolution and required threshold energy for polymerization. The applied polymerization model allows prediction of fabrication conditions and resulting fabrication size, alleviating the application of proteinaceous structure fabrication.

  19. Design, synthesis of novel antifungal triazole derivatives with high activities against Aspergillus fumigatus

    Institute of Scientific and Technical Information of China (English)

    Qiu Qin He; Chao Mei Liu; Ke Li; Yong Bing Cao

    2007-01-01

    Based on the active site of Aspergillusfumigatus lanosterol 14α-demethylase (AF-CYP51), novel triazole compounds were designed. Their chemical synthesis and the antifungal activities were reported. The results showed that all the target compounds exhibited excellent activities with broad spectrum; in which compounds 4, 12 and 15 showed comparable activities against A.fumigatus to the control drug itraconazole.

  20. Broad Spectrum Anti-Quorum Sensing Activity of Tannin-Rich Crude Extracts of Indian Medicinal Plants

    Directory of Open Access Journals (Sweden)

    Varsha Shukla

    2016-01-01

    Full Text Available Quorum sensing (QS mechanisms have been demonstrated to have significance in expression of pathogenicity in infectious bacteria. In Gram negative bacteria the autoinducer molecules that mediate QS are acyl homoserine lactones (AHL and in Gram positive bacteria they are peptides called autoinducing peptides (AIP. A screening of tannin-rich medicinal plants was attempted to identify extracts that could interrupt the QS mechanisms in both Gram positive and Gram negative bacteria over a wide range of concentrations and therefore potentially be potent agents that could act as broad spectrum QS inhibitors. Six out of the twelve Indian medicinal plant extracts that were analyzed exhibited anti-QS activity in Chromobacterium violaceum 12472 and in S. aureus strain with agr:blaZ fusion over a broad range of subinhibitory concentrations, indicating that the extracts contain high concentration of molecules that can interfere with the QS mechanisms mediated by AHL as well as AIP.

  1. Toxicity modulation, resistance enzyme evasion, and A-site X-ray structure of broad-spectrum antibacterial neomycin analogs.

    Science.gov (United States)

    Maianti, Juan Pablo; Kanazawa, Hiroki; Dozzo, Paola; Matias, Rowena D; Feeney, Lee Ann; Armstrong, Eliana S; Hildebrandt, Darin J; Kane, Timothy R; Gliedt, Micah J; Goldblum, Adam A; Linsell, Martin S; Aggen, James B; Kondo, Jiro; Hanessian, Stephen

    2014-09-19

    Aminoglycoside antibiotics are pseudosaccharides decorated with ammonium groups that are critical for their potent broad-spectrum antibacterial activity. Despite over three decades of speculation whether or not modulation of pKa is a viable strategy to curtail aminoglycoside kidney toxicity, there is a lack of methods to systematically probe amine-RNA interactions and resultant cytotoxicity trends. This study reports the first series of potent aminoglycoside antibiotics harboring fluorinated N1-hydroxyaminobutyryl acyl (HABA) appendages for which fluorine-RNA contacts are revealed through an X-ray cocrystal structure within the RNA A-site. Cytotoxicity in kidney-derived cells was significantly reduced for the derivative featuring our novel β,β-difluoro-HABA group, which masks one net charge by lowering the pKa without compromising antibacterial potency. This novel side-chain assists in evasion of aminoglycoside-modifying enzymes, and it can be easily transferred to impart these properties onto any number of novel analogs.

  2. Mussel-inspired synthesis of polydopamine-functionalized graphene oxide hydrogel as broad-spectrum antimicrobial material

    Science.gov (United States)

    Wang, Xinpeng; Liu, Zhiming; Zhong, Huiqing; Guo, Zhouyi; Yuan, Xiaochan

    2014-09-01

    Recently, three-dimensional GO-based hydrogels have attracted great attention due to the unique advantages. It is generally know that bacteria are everywhere and many of them could cause the diseases and threaten human health. However, developing new antibacterial materials with high-efficiency, low cost, broad-spectrum, and easy recycling is still a great challenge. Herein, inspired by mussel, we synthesized benzalkonium bromide/polydopamine/reduced graphene oxide hydrogel (BKB/PDA/rGOG). The as-prepared three-dimensional hydrogels were characterized by scanning eletron microscope (SEM), Fourier transform infrared spectroscopy (FT-IR) and Raman spectroscopy. The resultant hydrogels exhibited strong antibacterial effects to both Gram-negative and Gram-positive bacteria due to the synergistic effect of graphene oxide and benzalkonium bromide. In addition, the resultant hydrogels could be removed easily from the resolution, which was undoubtedly good news for industry application.

  3. “If it’s a broad spectrum, it can shoot better”: inappropriate antibiotic prescribing in Cambodia

    Directory of Open Access Journals (Sweden)

    Chhorvoin Om

    2016-12-01

    Full Text Available Abstract Background Cambodia is affected by antibiotic resistance but interventions to reduce the level of resistance require knowledge of the phenomena that lead to inappropriate prescribing. We interviewed physicians working in public hospitals to explore the drivers of inappropriate antibiotic prescribing. Methods Hospitals participating in a knowledge, attitudes and practices survey prior to this study were purposively selected and physicians were randomly recruited to participate in focus group discussions. Nvivo version 10 was used to inductively code the qualitative transcripts and manage thematic data analysis. Results Inappropriate antibiotic prescribing was a common practice and driven by seven factors: prescribing habit, limited diagnostic capacity, lack of microbiology evidence, non-evidence-based clinical guidelines, perceived patient demand, poor hygiene and infection control, and perceived bacterial resistance to narrow spectrum antibiotics. “Every day, doctors are not performing appropriately. We have made lots of mistakes with our antibiotic prescribing.” When a patient’s clinical condition was not responsive to empiric treatment, physicians changed to a broader spectrum antibiotic and microbiology services were sought only after failure of a treatment with a broad-spectrum antibiotic. This habitual empirical prescribing was a common practice regardless of microbiology service accessibility. Poor hygiene and infection control practices were commonly described as reasons for ‘preventive’ prescribing with full course of antibiotics while perception of bacterial resistance to narrow-spectrum antibiotics due to unrestricted access in the community resulted in unnecessary prescribing of broad spectrum antibiotics in private practices. Conclusions The practice of prescribing antibiotics by Cambodian physicians is inappropriate and based on prescribing habit rather than microbiology evidence. Improvement in prescribing

  4. Vancomycin and Five Broad-spectrum Antibiotic Utilization Evaluation in an Educational Medical Center in One Year

    Directory of Open Access Journals (Sweden)

    SiminDokht Shoaei

    2015-10-01

    Full Text Available  Background: Antibiotics can be life saving if they are used correctly, and can have unwanted side effects specially resistance with incorrect use. Unfortunately in fear of no response, physicians use broad spectrum antibiotics meticulously. In this Drug Utilization Evaluation (DUE, improper use of Vancomycin and five broad-spectrum antibiotics are studied to find faults and solution for this problem. Methods:This descriptive cross-sectional study performed during the March of 2012 to March of 2013.DUE of Imipenem, Meropenem, Piperacillin-Tazobactam, Cefepime, Ciprofloxacin and Vancomycin was done in 6 wards of Imam Hossein Hospital in Tehran. Demographic, clinical, laboratory, imaging and treatment data were looked for in medical records of 686 patients. Evaluation was done by three infectious disease specialist based on reference text book of Mandell’s Principles and Practice of Infectious Diseases 2010 and IDSA Guidelines. Results:This study showed 38.5% of prescriptions were correct and the remained 61.5% were incorrect with different faults predominantly incorrect overuse in 51.1%.Ciprofloxacin was the most common incorrect used drug in 74.8% cases and Piperacillin-Tazobactam with 48.7% cases had the least common incorrect use. There was no fault in prescription of antibiotics observing age and sex (pregnancy, breast feeding factors. Conclusions:Our results reveal a significant high level of the inappropriate use of Antibiotics mostly as overuse and empirically without culture results. It is needed to establish continuing medical education (CME courses and a locally conformable guideline of antibiotic use based on antibiogram results.

  5. A Strategy for Generating a Broad-Spectrum Monoclonal Antibody and Soluble Single-Chain Variable Fragments against Plant Potyviruses.

    Science.gov (United States)

    Liu, Han-Lin; Lin, Wei-Fang; Hu, Wen-Chi; Lee, Yung-An; Chang, Ya-Chun

    2015-10-01

    Potyviruses are major pathogens that often cause mixed infection in calla lilies. To reduce the time and cost of virus indexing, a detection method for the simultaneous targeting of multiple potyviruses was developed by generating a broad-spectrum monoclonal antibody (MAb) for detecting the greatest possible number of potyviruses. The conserved 121-amino-acid core regions of the capsid proteins of Dasheen mosaic potyvirus (DsMV), Konjak mosaic potyvirus (KoMV), and Zantedeschia mild mosaic potyvirus (ZaMMV) were sequentially concatenated and expressed as a recombinant protein for immunization. After hybridoma cell fusion and selection, one stable cell line that secreted a group-specific antibody, named C4 MAb, was selected. In the reaction spectrum test, the C4 MAb detected at least 14 potyviruses by indirect enzyme-linked immunosorbent assay (I-ELISA) and Western blot analysis. Furthermore, the variable regions of the heavy (VH) and light (VL) chains of the C4 MAb were separately cloned and constructed as single-chain variable fragments (scFvs) for expression in Escherichia coli. Moreover, the pectate lyase E (PelE) signal peptide of Erwinia chrysanthemi S3-1 was added to promote the secretion of C4 scFvs into the medium. According to Western blot analysis and I-ELISA, the soluble C4 scFv (VL-VH) fragment showed a binding specificity similar to that of the C4 MAb. Our results demonstrate that a recombinant protein derived from fusion of the conserved regions of viral proteins has the potential to produce a broad-spectrum MAb against a large group of viruses and that the PelE signal peptide can improve the secretion of scFvs in E. coli.

  6. Current antifungal treatment of fusariosis.

    Science.gov (United States)

    Al-Hatmi, Abdullah M S; Bonifaz, Alexandro; Ranque, Stephane; de Hoog, G Sybren; Verweij, Paul E; Meis, Jacques F

    2017-07-10

    Fungi of the genus Fusarium are well known as major plant pathogens and soil inhabitants but also cause a broad spectrum of human infections. Fusariosis is the second most common mould infection after aspergillosis and keratitis is the most encountered implantation infection in immunocompetent individuals. Natamycin is active against Fusarium species both in vitro and in vivo, and it is used along with voriconazole as the mainstay of treatment for Fusarium keratitis. Onychomycosis is treated with terbinafine, voriconazole and sometimes itraconazole. Cure is possible despite high in vitro MICs. Recently disseminated infections have increased dramatically, mainly affecting severely immunocompromised patients. The remarkable intrinsic resistance of Fusarium species to most antifungal agents results in high mortality rates in this patient population. Recovery of neutropenia is essential for patient survival and treatment should include voriconazole or amphotericin B as first line and posaconazole as salvage therapy. Copyright © 2017. Published by Elsevier B.V.

  7. New targets and delivery systems for antifungal therapy.

    Science.gov (United States)

    Walsh, T J; Viviani, M A; Arathoon, E; Chiou, C; Ghannoum, M; Groll, A H; Odds, F C

    2000-01-01

    Development of new approaches for treatment of invasive fungal infections encompasses new delivery systems for approved and investigational compounds, as well as exploiting the cell membrane, cell wall and virulence factors as putative antifungal targets. Novel delivery systems consisting of cyclodextrins, cochleates, nanoparticles/nanospheres and long circulating ('stealth') liposomes, substantially modulate the pharmacokinetics of existing compounds, and may also be useful to enhance the delivery of antifungal agents to sites of infection. Further insights into the structure-activity relationship of the antifungal triazoles that target the biosynthesis of ergosterol in the fungal cell membrane have led to the development of highly potent broad spectrum agents, including posaconazole, ravuconazole and voriconazole. Similarly, a novel generation of cell-wall active semisynthetic echinocandin 1,3 beta-glucan inhibitors (caspofungin, FK463, and VER-002) has entered clinical development. These agents have potent and broad-spectrum activity against Candida spp, and potentially useful activity against Aspergillus spp. and Pneumocystis carinii. The ongoing convergence of the fields of molecular pathogenesis, antifungal pharmacology and vaccine development will afford the opportunity to develop novel targets to complement the existing antifungal armamentarium.

  8. A multicenter comparative study of cefepime versus broad-spectrum antibacterial therapy in moderate and severe bacterial infections

    Directory of Open Access Journals (Sweden)

    Badaró Roberto

    2002-01-01

    Full Text Available The safety and efficacy of cefepime empiric monotherapy compared with standard broad-spectrum combination therapy for hospitalized adult patients with moderate to severe community-acquired bacterial infections were evaluated. In an open-label, multicenter study, 317 patients with an Acute Physiology and Chronic Health Evaluation (APACHE II score ranging from >5 to =19 were enrolled with documented pneumonia (n=196, urinary tract infection (n=65, intra-abdominal infection (n=38, or sepsis (n=18. Patients were randomly assigned 1:1 to receive cefepime 1 to 2 g IV twice daily or three times a day or IV ampicillin, cephalothin, or ceftriaxone ± aminoglycoside therapy for 3 to 21 days. For both treatment groups, metronidazole, vancomycin, or macrolide therapy was added as deemed necessary. The primary efficacy variable was clinical response at the end of therapy. Two hundred ninety-six (93% patients met evaluation criteria and were included in the efficacy analysis. Diagnoses included the following: 180 pneumonias (90 cefepime, 90 comparator, 62 urinary tract infections (29 cefepime, 33 comparator, 37 intra-abdominal infections (19 cefepime, 18 comparator, and 17 sepses (8 cefepime, 9 comparator. At the end of therapy, overall clinical success rates were 131/146 (90% for patients treated with cefepime vs 125/150 (83% for those treated with comparator (95% confidence interval [CI]: - 2.6% to 16.3%. The clinical success rate for patients with community-acquired pneumonia, the most frequent infection, was 86% for both treatment groups. Among the patients clinically evaluated, 162 pathogens were isolated and identified before therapy. The most commonly isolated pathogens were Escherichia coli (n=49, Streptococcus pneumoniae (n=29, Haemophilus influenzae (n=14, and Staphylococcus aureus (n=11. Bacteriologic eradication/presumed eradication was 97% for cefepime vs 94% for comparator-treated patients. Drug-related adverse events were reported in 16% of

  9. New insights into broad spectrum communities of the Early Holocene Near East: The birds of Hallan Çemi

    Science.gov (United States)

    Zeder, Melinda A.; Spitzer, Megan D.

    2016-11-01

    The Early Holocene in Near East was a pivotal transitional period that witnessed dramatic changes in climate and environment, human settlement, major changes in subsistence strategies focusing on a broad range of different plant and animal resources, and a radical restructuring of social relations. The remarkable corpus of avifauna from the Early Holocene site of Hallan Çemi in southeastern Turkey sheds new light on key issues about this dynamic period that has been termed the ;Broad Spectrum Revolution;. The avifauna from this important site demonstrate how Hallan Çemi occupants took advantage of the site's strategic location at the junction of multiple environmental zones by extracting a diverse range of seasonally available resources from both near-by and more distant eco-zones to cobble together a stable subsistence economy capable of supporting this small community throughout the year. They give testimony to the impacts of resource utilization over time, especially on species unable to rebound from sustained human hunting. At the same time, they show how Hallan Çemi residents mitigated these impacts by replacing depleted resources with alternative, more resilient ones that could be more sustainably harvested. They open a window onto the growing investment in feasting and ritual activity that helped bind this community together. In so doing they provide a means of empirically evaluating the efficacy of contrasting explanatory frameworks for the Broad Spectrum Revolution that gave rise to the subsequent domestication of plant and animals in the Near East. Contrary to frameworks that cast these developments as responses to resource depression, lessons learned from the Hallan Çemi avifauna lend support to frameworks that emphasize the human capacity to strategically target, capitalize, and improve upon circumscribed resource rich environments in a way that permits more permanent occupation of these niches. And they underscore the degree to which social and

  10. The broad-spectrum metalloproteinase inhibitor BB-94 inhibits growth, HER3 and Erk activation in fulvestrant-resistant breast cancer cell lines

    DEFF Research Database (Denmark)

    Kirkegaard, Tove; Yde, Christina Westmose; Kveiborg, Marie

    2014-01-01

    cells. This was prevented by treatment of resistant cells with the metalloproteinase inhibitor TAPI-2. Only the broad-spectrum metalloproteinase inhibitor BB-94, and not the more selective inhibitors GM6001 or TAPI-2, which inhibited shedding of the HER ligands produced by the fulvestrant...... of ligands. Only the broad-spectrum metalloproteinase inhibitor BB-94 could abrogate HER3 and Erk activation in the resistant cells, which stresses the complexity of the resistance mechanisms and the requirement of targeting signaling from HER receptors by multiple strategies....

  11. The Tortoise and the Hare. Small-Game Use, the Broad-Spectrum Revolution, and Paleolithic Demography.

    Science.gov (United States)

    Stiner; Munro; Surovell

    2000-02-01

    This study illustrates the potential of small-game data for identifying and dating Paleolithic demographic pulses such as those associated with modern human origins and the later evolution of food-producing economies. Archaeofaunal series from Israel and Italy serve as our examples. Three important implications of this study are that (1) early Middle Paleolithic populations were exceptionally small and highly dispersed, (2) the first major population growth pulse in the eastern Mediterranean probably occurred before the end of the Middle Paleolithic, and (3) subsequent demographic pulses in the Upper and Epi-Paleolithic greatly reshaped the conditions of selection that operated on human subsistence ecology, technology, and society. The findings of this study are consistent with the main premise of Flannery's broad-spectrum-revolution hypothesis. However, ranking small prey in terms of work of capture (in the absence of special harvesting tools) proved far more effective in this investigation of human diet breadth than have the taxonomic-diversity analyses published previously.

  12. The broad-spectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset.

    Science.gov (United States)

    Safronetz, David; Rosenke, Kyle; Westover, Jonna B; Martellaro, Cynthia; Okumura, Atsushi; Furuta, Yousuke; Geisbert, Joan; Saturday, Greg; Komeno, Takashi; Geisbert, Thomas W; Feldmann, Heinz; Gowen, Brian B

    2015-10-12

    With up to 500,000 infections annually, Lassa virus (LASV), the cause of Lassa fever, is one of the most prevalent etiological agents of viral hemorrhagic fever (VHF) in humans. LASV is endemic in several West African countries with sporadic cases and prolonged outbreaks observed most commonly in Sierra Leone, Liberia, Guinea and Nigeria. Additionally several cases of Lassa fever have been imported into North America, Europe and Asia making LASV a global threat to public health. Despite this, currently no approved therapeutic or vaccine exists to treat or prevent LASV infections. Here, using a passaged strain of LASV that is uniformly lethal in Hartley guinea pigs, we demonstrate that favipiravir, a broad-spectrum antiviral agent and leading treatment option for influenza, has potent activity against LASV infection. In this model, once daily treatment with favipiravir significantly reduced viral titers in tissue samples and reduced mortality rates when compared with animals receiving vehicle-only or ribavirin, the current standard of care for Lassa fever. Favipiravir remained highly effective against lethal LASV infection when treatments were initiated nine days post-infection, a time when animals were demonstrating advanced signs of disease. These results support the further preclinical evaluation of favipiravir for Lassa fever and other VHFs.

  13. Sedaxane, Isopyrazam and Solatenol™: Novel Broad-spectrum Fungicides Inhibiting Succinate Dehydrogenase (SDH) - Synthesis Challenges and Biological Aspects.

    Science.gov (United States)

    Walter, Harald; Tobler, Hans; Gribkov, Denis; Corsi, Camilla

    2015-01-01

    Sedaxane (SDX) 1, isopyrazam (IZM) 2 and Solatenol™ (STL) 3 are broad-spectrum pyrazole carboxamides, which originate from novel chemical classes of fungicides. Their mode of action (MoA) is inhibition of succinate dehydrogenase (SDH), which was recognized for a long time to deliver only compounds with a narrow biological spectrum. This view changed with the market introduction of BASF's boscalid in 2003. All major agro-companies subsequently worked in parallel on this MoA successfully and recently introduced new compounds to the market. Syngenta entered the SDHI area in 1998 and was able to introduce three complementary compounds to the market between 2010 and 2012. In this short review some synthesis challenges and biological effects of SDX 1, IZM 2 and STL 3 will be covered. New cost-efficient synthesis strategies for the preparation of o-biscyclopropyl-aniline, new benzonorbornene intermediates and the key pyrazole carboxylic acid intermediate which is essential for all three Syngenta SDHIs, will be in the focus of this review.

  14. A novel alkaloid from marine-derived actinomycete Streptomyces xinghaiensis with broad-spectrum antibacterial and cytotoxic activities.

    Directory of Open Access Journals (Sweden)

    Wence Jiao

    Full Text Available Due to the increasing emergence of drug-resistant bacteria and tumor cell lines, novel antibiotics with antibacterial and cytotoxic activities are urgently needed. Marine actinobacteria are rich sources of novel antibiotics, and here we report the discovery of a novel alkaloid, xinghaiamine A, from a marine-derived actinomycete Streptomyces xinghaiensis NRRL B24674(T. Xinghaiamine A was purified from the fermentation broth, and its structure was elucidated based on extensive spectroscopic analysis, including 1D and 2D NMR spectrum as well as mass spectrometry. Xinghaiamine A was identified to be a novel alkaloid with highly symmetric structure on the basis of sulfoxide functional group, and sulfoxide containing compound has so far never been reported in microorganisms. Biological assays revealed that xinghaiamine A exhibited broad-spectrum antibacterial activities to both Gram-negative persistent hospital pathogens (e.g. Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli and Gram-positive ones, which include Staphylococcus aureus and Bacillus subtilis. In addition, xinghaiamine A also exhibited potent cytotoxic activity to human cancer cell lines of MCF-7 and U-937 with the IC50 of 0.6 and 0.5 µM, respectively.

  15. Expression and post-translational processing of a broad-spectrum organophosphorus-neurotoxin-degrading enzyme in insect tissue culture

    Energy Technology Data Exchange (ETDEWEB)

    Dave, K.I.; Phillips, L.; Luckow, V.A.; Wild, J.R.

    1994-12-31

    A recombinant baculovirus, Autographa californica nuclear polyhedrosis virus (AcNPV), has been utilized to express the opd (organophosphate-degrading) gene from Pseudomonas diminuta in insect tissue-culture cells (Sf9) of the fall armyworm (Spodoptera frugiperda). The broad-spectrum organophosphate hydrolase (EC 3.1.8.1) encoded by this gene is a member of a general class of enzymes (organophosphate (OP) anhyorolases) that include parathion hydrolases, di-isopropyl-fluorophosphatases (DFpases), somanases, and OP phosphotrlesterases. This particular enzyme possesses the ability to hydrolyse paraoxon (P-O bond), DFP, sarin (P-F bond), VX (P-S bond) and tabun (P-CN bond), as well as a number of other extensively used organophosphorus pesticides. The enzyme produced in infected Sf9 cells is post-translationally processed and resembles the mature form of the enzyme expressed in various bacterial cells as identified by immunoprecipitation on Western blots. N-terminal sequence analysis of enzyme expressed in insect cells revealed Gly-29 as the terminal residue, whereas expression in Escherichia coli removes this residue, exposing Ser-30 at the N-terminus. Conditions for optimal expression of the enzyme in this system are described. Furthermore, hydrolytic efficiency of some OPs with purified enzyme from this system is discussed in relation to the in situ activity of Pseudomonas diminuta MG cells.

  16. A broad-spectrum, efficient and nontransgenic approach to control plant viruses by application of salicylic acid and jasmonic acid.

    Science.gov (United States)

    Shang, Jing; Xi, De-Hui; Xu, Fei; Wang, Shao-Dong; Cao, Sen; Xu, Mo-Yun; Zhao, Ping-Ping; Wang, Jian-Hui; Jia, Shu-Dan; Zhang, Zhong-Wei; Yuan, Shu; Lin, Hong-Hui

    2011-02-01

    Plant viruses cause many diseases that lead to significant economic losses. However, most of the approaches to control plant viruses, including transgenic processes or drugs are plant-species-limited or virus-species-limited, and not very effective. We introduce an application of jasmonic acid (JA) and salicylic acid (SA), a broad-spectrum, efficient and nontransgenic method, to improve plant resistance to RNA viruses. Applying 0.06 mM JA and then 0.1 mM SA 24 h later, enhanced resistance to Cucumber mosaic virus (CMV), Tobacco mosaic virus (TMV) and Turnip crinkle virus (TCV) in Arabidopsis, tobacco, tomato and hot pepper. The inhibition efficiency to virus replication usually achieved up to 80-90%. The putative molecular mechanism was investigated. Some possible factors affecting the synergism of JA and SA have been defined, including WRKY53, WRKY70, PDF1.2, MPK4, MPK2, MPK3, MPK5, MPK12, MPK14, MKK1, MKK2, and MKK6. All genes involving in the synergism of JA and SA were investigated. This approach is safe to human beings and environmentally friendly and shows potential as a strong tool for crop protection against plant viruses.

  17. Broad-spectrum multi-modality image registration: from PET, CT, and MRI to autoradiography, microscopy, and beyond.

    Science.gov (United States)

    Zanzonico, P B

    2006-01-01

    Image registration and fusion are increasingly important components of both clinical and small-animal imaging and have lead to the development of a variety of pertinent hardware and software tools, including multi-modality, e.g. PET-CT, devices. At the same time, advances in microscopic imaging, including phosphor-plate digital autoradiography and immunohistochemistry, now allow ultra-high (sub-100 microm)-resolution molecular characterization of tissue sections. To date, however, in vivo imaging of intact subjects and ex vivo imaging of harvested tissues sections have remained separate and distinct, making it difficult to reliably inter-compare the former and the latter. The Department of Medical Physics and the Radiation Biophysics Laboratory at Memorial Sloan-Kettering Cancer Center, under the direction of Dr. Clifton Ling, has now designed, fabricated, and tested a stereotactic imaging system for so-called "broad-spectrum" image registration, from coarser-resolution in vivo imaging modalities such as PET, CT, and MRI to ultra-high-resolution ex vivo imaging techniques such as histology, autoradiography, and immunohistochemistry.

  18. Rational design of broad spectrum antibacterial activity based on a clinically relevant enoyl-acyl carrier protein (ACP) reductase inhibitor.

    Science.gov (United States)

    Schiebel, Johannes; Chang, Andrew; Shah, Sonam; Lu, Yang; Liu, Li; Pan, Pan; Hirschbeck, Maria W; Tareilus, Mona; Eltschkner, Sandra; Yu, Weixuan; Cummings, Jason E; Knudson, Susan E; Bommineni, Gopal R; Walker, Stephen G; Slayden, Richard A; Sotriffer, Christoph A; Tonge, Peter J; Kisker, Caroline

    2014-06-06

    Determining the molecular basis for target selectivity is of particular importance in drug discovery. The ideal antibiotic should be active against a broad spectrum of pathogenic organisms with a minimal effect on human targets. CG400549, a Staphylococcus-specific 2-pyridone compound that inhibits the enoyl-acyl carrier protein reductase (FabI), has recently been shown to possess human efficacy for the treatment of methicillin-resistant Staphylococcus aureus infections, which constitute a serious threat to human health. In this study, we solved the structures of three different FabI homologues in complex with several pyridone inhibitors, including CG400549. Based on these structures, we rationalize the 65-fold reduced affinity of CG400549 toward Escherichia coli versus S. aureus FabI and implement concepts to improve the spectrum of antibacterial activity. The identification of different conformational states along the reaction coordinate of the enzymatic hydride transfer provides an elegant visual depiction of the relationship between catalysis and inhibition, which facilitates rational inhibitor design. Ultimately, we developed the novel 4-pyridone-based FabI inhibitor PT166 that retained favorable pharmacokinetics and efficacy in a mouse model of S. aureus infection with extended activity against Gram-negative and mycobacterial organisms. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. Rational Design of Broad Spectrum Antibacterial Activity Based on a Clinically Relevant Enoyl-Acyl Carrier Protein (ACP) Reductase Inhibitor*

    Science.gov (United States)

    Schiebel, Johannes; Chang, Andrew; Shah, Sonam; Lu, Yang; Liu, Li; Pan, Pan; Hirschbeck, Maria W.; Tareilus, Mona; Eltschkner, Sandra; Yu, Weixuan; Cummings, Jason E.; Knudson, Susan E.; Bommineni, Gopal R.; Walker, Stephen G.; Slayden, Richard A.; Sotriffer, Christoph A.; Tonge, Peter J.; Kisker, Caroline

    2014-01-01

    Determining the molecular basis for target selectivity is of particular importance in drug discovery. The ideal antibiotic should be active against a broad spectrum of pathogenic organisms with a minimal effect on human targets. CG400549, a Staphylococcus-specific 2-pyridone compound that inhibits the enoyl-acyl carrier protein reductase (FabI), has recently been shown to possess human efficacy for the treatment of methicillin-resistant Staphylococcus aureus infections, which constitute a serious threat to human health. In this study, we solved the structures of three different FabI homologues in complex with several pyridone inhibitors, including CG400549. Based on these structures, we rationalize the 65-fold reduced affinity of CG400549 toward Escherichia coli versus S. aureus FabI and implement concepts to improve the spectrum of antibacterial activity. The identification of different conformational states along the reaction coordinate of the enzymatic hydride transfer provides an elegant visual depiction of the relationship between catalysis and inhibition, which facilitates rational inhibitor design. Ultimately, we developed the novel 4-pyridone-based FabI inhibitor PT166 that retained favorable pharmacokinetics and efficacy in a mouse model of S. aureus infection with extended activity against Gram-negative and mycobacterial organisms. PMID:24739388

  20. Patients with McCune-Albright syndrome have a broad spectrum of abnormalities in the gastrointestinal tract and pancreas.

    Science.gov (United States)

    Wood, Laura D; Noë, Michaël; Hackeng, Wenzel; Brosens, Lodewijk A A; Bhaijee, Feriyl; Debeljak, Marija; Yu, Jun; Suenaga, Masaya; Singhi, Aatur D; Zaheer, Atif; Boyce, Alison; Robinson, Cemre; Eshleman, James R; Goggins, Michael G; Hruban, Ralph H; Collins, Michael T; Lennon, Anne Marie; Montgomery, Elizabeth A

    2017-02-10

    McCune-Albright Syndrome (MAS) is a rare sporadic syndrome caused by post-zygotic mutations in the GNAS oncogene, leading to constitutional mosaicism for these alterations. Somatic activating GNAS mutations also commonly occur in several gastrointestinal and pancreatic neoplasms, but the spectrum of abnormalities in these organs in patients with MAS has yet to be systematically described. We report comprehensive characterization of the upper gastrointestinal tract in seven patients with MAS and identify several different types of polyps, including gastric heterotopia/metaplasia (7/7), gastric hyperplastic polyps (5/7), fundic gland polyps (2/7), and a hamartomatous polyp (1/7). In addition, one patient had an unusual adenomatous lesion at the gastroesophageal junction with high-grade dysplasia. In the pancreas, all patients had endoscopic ultrasound findings suggestive of intraductal papillary mucinous neoplasm (IPMN), but only two patients met the criteria for surgical intervention. Both of these patients had IPMNs at resection, one with low-grade dysplasia and one with high-grade dysplasia. GNAS mutations were identified in the majority of lesions analyzed, including both IPMNs and the adenomatous lesion from the gastroesophageal junction. These studies suggest that there is a broad spectrum of abnormalities in the gastrointestinal tract and pancreas in patients with MAS and that patients with MAS should be evaluated for gastrointestinal pathology, some of which may warrant clinical intervention due to advanced dysplasia.

  1. Marker-assisted introgression of broad-spectrum blast resistance genes into the cultivated MR219 rice variety.

    Science.gov (United States)

    Miah, Gous; Rafii, Mohd Y; Ismail, Mohd R; Puteh, Adam B; Rahim, Harun A; Latif, Mohammad A

    2017-07-01

    The rice cultivar MR219 is famous for its better yield and long and fine grain quality; however, it is susceptible to blast disease. The main objective of this study was to introgress blast resistance genes into MR219 through marker-assisted selection (MAS). The rice cultivar MR219 was used as the recurrent parent, and Pongsu Seribu 1 was used as the donor. Marker-assisted foreground selection was performed using RM6836 and RM8225 to identify plants possessing blast resistance genes. Seventy microsatellite markers were used to estimate recurrent parent genome (RPG) recovery. Our analysis led to the development of 13 improved blast resistant lines with Piz, Pi2 and Pi9 broad-spectrum blast resistance genes and an MR219 genetic background. The RPG recovery of the selected improved lines was up to 97.70% with an average value of 95.98%. Selected improved lines showed a resistance response against the most virulent blast pathogen pathotype, P7.2. The selected improved lines did not express any negative effect on agronomic traits in comparison with MR219. The research findings of this study will be a conducive approach for the application of different molecular techniques that may result in accelerating the development of new disease-resistant rice varieties, which in turn will match rising demand and food security worldwide. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

  2. ICF syndrome mutations cause a broad spectrum of biochemical defects in DNMT3B-mediated de novo DNA methylation.

    Science.gov (United States)

    Moarefi, Amir H; Chédin, Frédéric

    2011-06-24

    The DNMT3B de novo DNA methyltransferase (DNMT) plays a major role in establishing DNA methylation patterns in early mammalian development, but its catalytic mechanism remains poorly characterized. Here, we provide a comprehensive biochemical analysis of human DNMT3B function through the characterization of a series of site-directed DNMT3B variants associated with immunodeficiency, centromere instability, and facial anomalies (ICF) syndrome. Our data reveal several novel and important aspects of DNMT3B function. First, DNMT3B, unlike DNMT3A, requires a DNA cofactor in order to stably bind to S-adenosyl-l-methionine (SAM), suggesting that it proceeds according to an ordered catalytic scheme. Second, ICF mutations cause a broad spectrum of biochemical defects in DNMT3B function, including defects in homo-oligomerization, SAM binding, SAM utilization, and DNA binding. Third, all tested ICF mutations, including the A766P and R840Q variants, result in altered catalytic properties without interfering with DNMT3L-mediated stimulation; this indicates that DNMT3L is not involved in the pathogenesis of ICF syndrome. Finally, our study reveals a novel level of coupling between substrate binding, oligomerization, and catalysis that is likely conserved within the DNMT3 family of enzymes.

  3. Novel Hybrid Anticonvulsants Derived from Pyrrolidine-2,5-dione Scaffold with Broad Spectrum of Activity in the Preclinical Studies.

    Science.gov (United States)

    Kaminski, Krzysztof

    2017-01-01

    The multifunctional ligands application is an emerging approach in drug delivery, mainly in the treatment of diseases with complex pathology, such as Alzheimer's, cancer, and epilepsy. Using this method many biomolecules with different properties are combined to form a single unit that can provide a complex broad spectrum activity. Thus, a new type of hybrid anticonvulsants based on the pyrrolidine-2,5-dione frame are detailed with the aim of acquiring more effective antiepileptic drugs (AED) that could suppress various human convulsions. These hybrid molecules attach to the chemical particles of clinically relevant AEDs such as ethosuximide, levetiracetam, and lacosamide. As a result of this hybridization process the compounds obtained were effective in three most important animal epilepsy models, namely the maximal electroshock seizure (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and the six-Hertz (6 Hz) model in mice. These substances displayed wider spectrum of protection, more potent efficacy, and better safety profile than the aforementioned AEDs. Several compounds were also active in the formalin model of persistent pain in mice. The in vitro ligand binding studies have proved that the most conceivable molecular mechanism of anticonvulsant and antinociceptive action was the influence on the neuronal voltage-sensitive sodium and L-type calcium channels. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Antifungal activity of traditional medicinal plants from Tamil Nadu, India

    Institute of Scientific and Technical Information of China (English)

    Duraipandiyan V; Ignacimuthu S

    2011-01-01

    Objective:To assess the antifungal activity of hexane, ethyl acetate and methanol extracts of 45 medicinal plants and to determine the minimum inhibitory concentration for each extract against human pathogenic fungi. Methods:A total of 45 medicinal plants were collected from different places of Tamil Nadu and identified. Hexane, ethyl acetate and methanol extracts of 45 medicinal plants were assessed for antifungal susceptibility using broth microdilution method. Two known antifungal agents were used as positive controls. Results: Most of the extracts inhibited more than four fungal strains. From the evaluation we found that ethyl acetate extracts inhibited large number of fungal growth. Hexane extracts also nearly showed the same level of inhibition against fungal growth. Methanol extracts showed the minimum antifungal activity. Among the 45 plants tested, broad spectrum antifungal activity was detected in Albizzia procera (A. procera), Atalantia monophylla, Asclepias curassavica, Azima tetracantha, Cassia fistula (C. fistula), Cinnomomum verum, Costus speciosus (C. speciosus), Nymphaea stellata, Osbeckia chinensis, Piper argyrophyllum, Punica granatum, Tinospora cordifolia and Toddalia asiatica (T. asiatica). Promising antifungal activity was seen in A. procera, C. speciosus, C. fistula and T. asiatica. Conclusions:It can be concluded that the plant species assayed possess antifungal properties. Further phytochemical research is needed to identify the active principles responsible for the antifungal effects of some of these medicinal plants.

  5. Durable broad-spectrum powdery mildew resistance in pea er1 plants is conferred by natural loss-of-function mutations in PsMLO1

    NARCIS (Netherlands)

    Humphry, M.; Reinstädler, A.; Ivanov, S.; Bisseling, T.; Panstruga, R.

    2011-01-01

    Loss-of-function alleles of plant-specific MLO (Mildew Resistance Locus O) genes confer broad-spectrum powdery mildew resistance in monocot (barley) and dicot (Arabidopsis thaliana, tomato) plants. Recessively inherited powdery mildew resistance in pea (Pisum sativum) er1 plants is, in many aspects,

  6. Comparison of nitroethane, 2-nitro-1-propanol, lauric acid, Lauricidin and the Hawaiian marine algae, Chaetoceros, for potential broad-spectrum control of anaerobically grown lactic acid bacteria

    Science.gov (United States)

    The gastrointestinal tract of bovines often contains bacteria that contribute to disorders of the rumen and may also contain foodborne or opportunistic human pathogens as well as bacteria capable of causing mastitis in cows. Thus, there is a need to develop broad-spectrum therapies that are effecti...

  7. A highly sensitive, multiplex broad-spectrum PCR-DNA-enzyme immunoassay and reverse hybridization assay for rapid detection and identification of Chlamydia trachomatis serovars.

    NARCIS (Netherlands)

    Quint, K.D.; Doorn, L.J. van; Kleter, B.; Koning, M.N. de; Munckhof, H.A. van den; Morre, S.A.; Harmsel, B. ter; Weiderpass, E.; Harbers, G.; Melchers, W.J.G.; Quint, W.G.V.

    2007-01-01

    Chlamydia trachomatis (Ct) comprises distinct serogroups and serovars. The present study evaluates a novel Ct amplification, detection, and genotyping method (Ct-DT assay). The Ct-DT amplification step is a multiplex broad-spectrum PCR for the cryptic plasmid and the VD2-region of ompl. The Ct-DT de

  8. Draft Genome Sequence of Streptomyces sp. Strain Wb2n-11, a Desert Isolate with Broad-Spectrum Antagonism against Soilborne Phytopathogens

    Energy Technology Data Exchange (ETDEWEB)

    Köberl, Martina; White, Richard A.; Erschen, Sabine; El-Arabi, Tarek F.; Jansson, Janet K.; Berg, Gabriele

    2015-08-06

    Streptomyces sp. strain Wb2n-11, isolated from native desert soil, exhibited broad-spectrum antagonism against plant pathogenic fungi, bacteria and nematodes. The 8.2 Mb draft genome reveals genes putatively responsible for its promising biocontrol activity and genes which enable the soil bacterium to directly interact beneficially with plants.

  9. Broad spectrum late blight resistance in potato differential set plants MaR8 and MaR9 is conferred by multiple stacked R genes

    NARCIS (Netherlands)

    Kim, H.I.; Lee, H.; Jo, K.R.; Mortazavian, S.M.M.; Huigen, D.J.; Evenhuis, A.; Kessel, G.J.T.; Visser, R.G.F.; Vossen, J.H.; Jacobsen, E.

    2012-01-01

    Phytophthora infestans is the causal agent of late blight in potato. The Mexican species Solanum demissum is well known as a good resistance source. Among the 11 R gene differentials, which were introgressed from S. demissum, especially R8 and R9 differentials showed broad spectrum resistance both u

  10. Naturally occurring broad-spectrum powdery mildw resistance in a central American tomato accession is caused by loss of Mlo function

    NARCIS (Netherlands)

    Bai, Y.; Pavan, S.N.C.; Zheng, Z.; Zappel, N.F.; Reinstadler, A.; Lotti, C.; Giovanni, de C.; Ricciardi, L.; Lindhout, P.; Visser, R.G.F.; Theres, K.; Panstruga, R.

    2008-01-01

    The resistant cherry tomato (Solanum lycopersicum var. cerasiforme) line LC-95, derived from an accession collected in Ecuador, harbors a natural allele (ol-2) that confers broad-spectrum and recessively inherited resistance to powdery mildew (Oidium neolycopersici). As both the genetic and phytopat

  11. Characterization of the UVA protection provided by avobenzone, zinc oxide, and titanium dioxide in broad-spectrum sunscreen products.

    Science.gov (United States)

    Beasley, Donathan G; Meyer, Thomas A

    2010-12-01

    Solar UV radiation (UVR) is composed of UVB (290-320 nm) and UVA (320-400 nm) wavelengths. Only two sunscreen active ingredients approved in the US, avobenzone (butylmethoxydibenzoylmethane) and zinc oxide (ZnO), provide true broad-spectrum protection against UVA wavelengths >360 nm. Although effective against shorter UVR wavelengths avobenzone. To sustain its absorption capacity within a sunscreen film during UVR exposure, avobenzone needs to be formulated into sunscreen products using sound formulation strategies. To characterize the efficacy of avobenzone, ZnO, and TiO(2) in terms of their abilities to provide broad UVA protection and to demonstrate the effectiveness of the different formulation strategies used today to maintain the efficacy of avobenzone even during prolonged exposures to UVR. UVA efficacy was assessed by measuring absorbance profiles in vitro using Vitro Skin® (IMS Inc., Orange, CT, USA) as an inert substrate and by determining UVA protection factors (PFA) on human skin. The impact of avobenzone loss on sun protection factor (SPF) and PFA values was evaluated by serially reducing avobenzone concentrations in an otherwise photostable product. The photostabilizing influence of specific formulation ingredients was monitored by measuring the extent to which they prevented UVR-induced degradation of avobenzone, whereas photostability of commercial sunscreen products was quantified by measuring the percentage change in absorbance within the UVB and UVA spectral regions following irradiation of thin product films on inert substrates. Model formulations containing 3% avobenzone or 5% ZnO provided superior attenuation of UVA wavelengths >360 nm compared with formulas containing 5% TiO(2). Additionally, sunscreen products of similar SPF containing avobenzone or ZnO exhibited significantly higher PFA values than those containing TiO(2). The addition of photostabilized avobenzone or ZnO increased PFA values nearly 3-fold, whereas the addition of

  12. The CD8-derived chemokine XCL1/lymphotactin is a conformation-dependent, broad-spectrum inhibitor of HIV-1.

    Directory of Open Access Journals (Sweden)

    Christina Guzzo

    Full Text Available CD8+ T cells play a key role in the in vivo control of HIV-1 replication via their cytolytic activity as well as their ability to secrete non-lytic soluble suppressive factors. Although the chemokines that naturally bind CCR5 (CCL3/MIP-1α, CCL4/MIP- 1β, CCL5/RANTES are major components of the CD8-derived anti-HIV activity, evidence indicates the existence of additional, still undefined, CD8-derived HIV-suppressive factors. Here, we report the characterization of a novel anti-HIV chemokine, XCL1/lymphotactin, a member of the C-chemokine family that is produced primarily by activated CD8+ T cells and behaves as a metamorphic protein, interconverting between two structurally distinct conformations (classic and alternative. We found that XCL1 inhibits a broad spectrum of HIV-1 isolates, irrespective of their coreceptor-usage phenotype. Experiments with stabilized variants of XCL1 demonstrated that HIV-1 inhibition requires access to the alternative, all-β conformation, which interacts with proteoglycans but does not bind/activate the specific XCR1 receptor, while the classic XCL1 conformation is inactive. HIV-1 inhibition by XCL1 was shown to occur at an early stage of infection, via blockade of viral attachment and entry into host cells. Analogous to the recently described anti-HIV effect of the CXC chemokine CXCL4/PF4, XCL1-mediated inhibition is associated with direct interaction of the chemokine with the HIV-1 envelope. These results may open new perspectives for understanding the mechanisms of HIV-1 control and reveal new molecular targets for the design of effective therapeutic and preventive strategies against HIV-1.

  13. Competition between Phytophthora infestans effectors leads to increased aggressiveness on plants containing broad-spectrum late blight resistance.

    Directory of Open Access Journals (Sweden)

    Dennis A Halterman

    Full Text Available BACKGROUND: The destructive plant disease potato late blight is caused by the oomycete pathogen Phytophthora infestans (Mont. de Bary. This disease has remained particularly problematic despite intensive breeding efforts to integrate resistance into cultivated potato, largely because of the pathogen's ability to quickly evolve to overcome major resistance genes. The RB gene, identified in the wild potato species S. bulbocastanum, encodes a protein that confers broad-spectrum resistance to most P. infestans isolates through its recognition of highly conserved members of the corresponding pathogen effector family IPI-O. IpiO is a multigene family of effectors and while the majority of IPI-O proteins are recognized by RB to elicit host resistance, some variants exist that are able to elude detection (e.g. IPI-O4. METHODS AND FINDINGS: In the present study, analysis of ipiO variants among 40 different P. infestans isolates collected from Guatemala, Thailand, and the United States revealed a high degree of complexity within this gene family. Isolate aggressiveness was correlated with increased ipiO diversity and especially the presence of the ipiO4 variant. Furthermore, isolates expressing IPI-O4 overcame RB-mediated resistance in transgenic potato plants even when the resistance-eliciting IPI-O1 variant was present. In support of this finding, we observed that expression of IPI-O4 via Agrobacterium blocked recognition of IPI-O1, leading to inactivation of RB-mediated programmed cell death in Nicotiana benthamiana. CONCLUSIONS: In this study we definitively demonstrate and provide the first evidence that P. infestans can defeat an R protein through inhibition of recognition of the corresponding effector protein.

  14. Exoproteome and secretome derived broad spectrum novel drug and vaccine candidates in Vibrio cholerae targeted by Piper betel derived compounds.

    Directory of Open Access Journals (Sweden)

    Debmalya Barh

    Full Text Available Vibrio cholerae is the causal organism of the cholera epidemic, which is mostly prevalent in developing and underdeveloped countries. However, incidences of cholera in developed countries are also alarming. Because of the emergence of new drug-resistant strains, even though several generic drugs and vaccines have been developed over time, Vibrio infections remain a global health problem that appeals for the development of novel drugs and vaccines against the pathogen. Here, applying comparative proteomic and reverse vaccinology approaches to the exoproteome and secretome of the pathogen, we have identified three candidate targets (ompU, uppP and yajC for most of the pathogenic Vibrio strains. Two targets (uppP and yajC are novel to Vibrio, and two targets (uppP and ompU can be used to develop both drugs and vaccines (dual targets against broad spectrum Vibrio serotypes. Using our novel computational approach, we have identified three peptide vaccine candidates that have high potential to induce both B- and T-cell-mediated immune responses from our identified two dual targets. These two targets were modeled and subjected to virtual screening against natural compounds derived from Piper betel. Seven compounds were identified first time from Piper betel to be highly effective to render the function of these targets to identify them as emerging potential drugs against Vibrio. Our preliminary validation suggests that these identified peptide vaccines and betel compounds are highly effective against Vibrio cholerae. Currently we are exhaustively validating these targets, candidate peptide vaccines, and betel derived lead compounds against a number of Vibrio species.

  15. Broad-spectrum sunscreens prevent the secretion of proinflammatory cytokines in human keratinocytes exposed to ultraviolet A and phototoxic lomefloxacin

    Energy Technology Data Exchange (ETDEWEB)

    Reinhardt, P.; Cybulski, M. [Lasers and Electro-Optics Div., Consumer and Clinical Radiation Protection Bureau, Product Safety Program, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario (Canada)], E-mail: pascale_reinhardt@hc-sc.gc.ca; Miller, S.M.; Ferrarotto, C.; Wilkins, R. [Radiobiology Div., Consumer and Clinical Radiation Protection Bureau, Product Safety Program, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario (Canada); Deslauriers, Y. [Lasers and Electro-Optics Div., Consumer and Clinical Radiation Protection Bureau, Product Safety Program, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario (Canada)

    2006-02-15

    The combination of phototoxic drugs and ultraviolet (UV) radiation can trigger the release of proinflammatory cytokines. The present study measured the ability of sunscreens to prevent cytokine secretion in human keratinocytes following cotreatment of these cells with a known photoreactive drug and UVA. Keratinocytes were treated for 1 h with increasing concentrations of lomefloxacin (LOM) or norfloxacin (NOR), exposed to 15 J/cm{sup 2} UVA, and incubated for 24 h. NOR, owing to the absence of a fluorine atom in position 8, was non-phototoxic and used as a negative control. Cell viability and the release of 3 cytokines were assessed, namely interleukin-1{alpha} (IL-1{alpha}), interleukin-6 (IL-6), and tumour necrosis factor-{alpha} (TNF-{alpha}). The measurement of these cytokines may be a useful tool for detecting photoreactive compounds. To measure their ability to prevent cytokine secretion, various sunscreens were inserted between the UVA source and the cells. Treatment with NOR, NOR plus UVA, or LOM had no effect on the cells. LOM plus UVA, however, had an effect on cell viability and on cytokine secretion. IL-1{alpha} levels increased with LOM concentration. The release of TNF-{alpha} and IL-6 followed the same pattern at lower concentrations of LOM but peaked at 15 {mu}mol/L and decreased at higher concentrations. Sunscreens protected the cells from the effects of LOM plus UVA, as cell viability and levels of cytokines remained the same as in the control cells. In conclusion, the application of broad-spectrum sunscreen by individuals exposed to UVA radiation may prevent phototoxic reactions initiated by drugs such as LOM. (author)

  16. Inhibition of an aquatic rhabdovirus demonstrates promise of a broad-spectrum antiviral for use in aquaculture

    Science.gov (United States)

    Balmer, Bethany F.; Powers, Rachel L.; Zhang, Ting-Hu; Lee, Jihye; Vigant, Frederic; Lee, Benhur; Jung, Michael E.; Purcell, Maureen K.; Snekvik, Kevin; Aguilar, Hector C.

    2017-01-01

    Many enveloped viruses cause devastating disease in aquaculture, resulting in significant economic impact. LJ001 is a broad-spectrum antiviral compound that inhibits enveloped virus infections by specifically targeting phospholipids in the lipid bilayer via the production of singlet oxygen (1O2). This stabilizes positive curvature and decreases membrane fluidity, which inhibits virus-cell membrane fusion during viral entry. Based on data from previous mammalian studies and the requirement of light for the activation of LJ001, we hypothesized that LJ001 may be useful as a preventative and/or therapeutic agent for infections by enveloped viruses in aquaculture. Here, we report that LJ001 was more stable with a prolonged inhibitory half-life at relevant aquaculture temperatures (15°C), than in mammalian studies at 37°C. When LJ001 was preincubated with our model virus, infectious hematopoietic necrosis virus (IHNV), infectivity was significantly inhibited in vitro (using the epithelioma papulosum cyprini [EPC] fish cell line) and in vivo (using rainbow trout fry) in a dose-dependent and time-dependent manner. While horizontal transmission of IHNV in a static cohabitation challenge model was reduced by LJ001, transmission was not completely blocked at established antiviral doses. Therefore, LJ001 may be best suited as a therapeutic for aquaculture settings that include viral infections with lower virus-shedding rates than IHNV or where higher viral titers are required to initiate infection of naive fish. Importantly, our data also suggest that LJ001-inactivated IHNV elicited an innate immune response in the rainbow trout host, making LJ001 potentially useful for future vaccination approaches.

  17. Reduced TiO2-Graphene Oxide Heterostructure As Broad Spectrum-Driven Efficient Water-Splitting Photocatalysts.

    Science.gov (United States)

    Li, Lihua; Yu, Lili; Lin, Zhaoyong; Yang, Guowei

    2016-04-06

    The reduced TiO2-graphene oxide heterostructure as an alternative broad spectrum-driven efficient water splitting photocatalyst has become a really interesting topic, however, its syntheses has many flaws, e.g., tedious experimental steps, time-consuming, small scale production, and requirement of various additives, for example, hydrazine hydrate is widely used as reductant to the reduction of graphene oxide, which is high toxicity and easy to cause the second pollution. For these issues, herein, we reported the synthesis of the reduced TiO2-graphene oxide heterostructure by a facile chemical reduction agent-free one-step laser ablation in liquid (LAL) method, which achieves extended optical response range from ultraviolet to visible and composites TiO(2-x) (reduced TiO2) nanoparticle and graphene oxide for promoting charge conducting. 30.64% Ti(3+) content in the reduced TiO2 nanoparticles induces the electronic reconstruction of TiO2, which results in 0.87 eV decrease of the band gap for the visible light absorption. TiO(2-x)-graphene oxide heterostructure achieved drastically increased photocatalytic H2 production rate, up to 23 times with respect to the blank experiment. Furthermore, a maximum H2 production rate was measured to be 16 mmol/h/g using Pt as a cocatalyst under the simulated sunlight irradiation (AM 1.5G, 135 mW/cm(2)), the quantum efficiencies were measured to be 5.15% for wavelength λ = 365 ± 10 nm and 1.84% for λ = 405 ± 10 nm, and overall solar energy conversion efficiency was measured to be 14.3%. These findings provided new insights into the broad applicability of this methodology for accessing fascinate photocatalysts.

  18. Broad spectrum infrared thermal desorption of wipe-based explosive and narcotic samples for trace mass spectrometric detection.

    Science.gov (United States)

    Forbes, Thomas P; Staymates, Matthew; Sisco, Edward

    2017-08-07

    Wipe collected analytes were thermally desorbed using broad spectrum near infrared heating for mass spectrometric detection. Employing a twin tube filament-based infrared emitter, rapid and efficiently powered thermal desorption and detection of nanogram levels of explosives and narcotics was demonstrated. The infrared thermal desorption (IRTD) platform developed here used multi-mode heating (direct radiation and secondary conduction from substrate and subsequent convection from air) and a temperature ramp to efficiently desorb analytes with vapor pressures across eight orders of magnitude. The wipe substrate experienced heating rates up to (85 ± 2) °C s(-1) with a time constant of (3.9 ± 0.2) s for 100% power emission. The detection of trace analytes was also demonstrated from complex mixtures, including plastic-bonded explosives and exogenous narcotics, explosives, and metabolites from collected artificial latent fingerprints. Manipulation of the emission power and duration directly controlled the heating rate and maximum temperature, enabling differential thermal desorption and a level of upstream separation for enhanced specificity. Transitioning from 100% power and 5 s emission duration to 25% power and 30 s emission enabled an order of magnitude increase in the temporal separation (single seconds to tens of seconds) of the desorption of volatile and semi-volatile species within a collected fingerprint. This mode of operation reduced local gas-phase concentrations, reducing matrix effects experienced with high concentration mixtures. IRTD provides a unique platform for the desorption of trace analytes from wipe collections, an area of importance to the security sector, transportation agencies, and customs and border protection.

  19. Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor.

    Science.gov (United States)

    Kim, Yunjeong; Liu, Hongwei; Galasiti Kankanamalage, Anushka C; Weerasekara, Sahani; Hua, Duy H; Groutas, William C; Chang, Kyeong-Ok; Pedersen, Niels C

    2016-03-01

    Coronaviruses infect animals and humans causing a wide range of diseases. The diversity of coronaviruses in many mammalian species is contributed by relatively high mutation and recombination rates during replication. This dynamic nature of coronaviruses may facilitate cross-species transmission and shifts in tissue or cell tropism in a host, resulting in substantial change in virulence. Feline enteric coronavirus (FECV) causes inapparent or mild enteritis in cats, but a highly fatal disease, called feline infectious peritonitis (FIP), can arise through mutation of FECV to FIP virus (FIPV). The pathogenesis of FIP is intimately associated with immune responses and involves depletion of T cells, features shared by some other coronaviruses like Severe Acute Respiratory Syndrome Coronavirus. The increasing risks of highly virulent coronavirus infections in humans or animals call for effective antiviral drugs, but no such measures are yet available. Previously, we have reported the inhibitors that target 3C-like protease (3CLpro) with broad-spectrum activity against important human and animal coronaviruses. Here, we evaluated the therapeutic efficacy of our 3CLpro inhibitor in laboratory cats with FIP. Experimental FIP is 100% fatal once certain clinical and laboratory signs become apparent. We found that antiviral treatment led to full recovery of cats when treatment was started at a stage of disease that would be otherwise fatal if left untreated. Antiviral treatment was associated with a rapid improvement in fever, ascites, lymphopenia and gross signs of illness and cats returned to normal health within 20 days or less of treatment. Significant reduction in viral titers was also observed in cats. These results indicate that continuous virus replication is required for progression of immune-mediated inflammatory disease of FIP. These findings may provide important insights into devising therapeutic strategies and selection of antiviral compounds for further

  20. A genetically modified broad-spectrum strain of Bacillus thuringiensis toxic against Holotrichia parallela, Anomala corpulenta and Holotrichia oblita.

    Science.gov (United States)

    Jia, Yanhua; Zhao, Can; Wang, Qinglei; Shu, Changlong; Feng, Xiaojie; Song, Fuping; Zhang, Jie

    2014-02-01

    Cry8Ea1 from Bacillus thuringiensis strain Bt185 has insecticidal activity against Holotrichia parallela. Cry8Ca2 from strain HBF-1 is effective against Anomala corpulenta. Cry8Ga1 from strain HBF-18 is toxic to H. oblita. Given the need to broaden the spectrum of B. thuringiensis, a broad-spectrum coleopteran active strain of B. thuringiensis, BIOT185, engineered to express multiple cry genes, including cry8Ea1, cry8Fa1 and cry8Ca2, was created by homologous recombination introducing the cry8Ca2 into the B. thuringiensis strain Bt185 by Liu et al. (Appl Microbiol Biotechnol 87:243-249, 2010). To further broaden the spectrum, an engineered B. thuringiensis strain BIOT1858G was constructed by introducing the recombinant plasmid pSTK-8G containing cry8Ga1 into the engineered B. thuringiensis strain BIOT185. PCR and Southern blotting demonstrated that the cry8Ga1 gene was transferred to the novel strain BIOT1858G. SDS-PAGE and RT-PCR confirmed the normal expression and transcription of the cry8Ga1 gene in addition to the cry8Ea1, cry8Fa1 and cry8Ca2 genes. Bioassays of BIOT1858G indicated that the recombinant strain broadened the spectrum against not only H. parallela susceptible to the Cry8E protein and A. corpulenta susceptible to the Cry8C protein but also H. oblita susceptible to the Cry8G protein. The pesticide could also decrease the cost of production and field labor.

  1. Spectral properties of plant leaves pertaining to urban landscape design of broad-spectrum solar ultraviolet radiation reduction.

    Science.gov (United States)

    Yoshimura, Haruka; Zhu, Hui; Wu, Yunying; Ma, Ruijun

    2010-03-01

    Human exposure to harmful ultraviolet (UV) radiation has important public health implications. Actual human exposure to solar UV radiation depends on ambient UV irradiance, and the latter is influenced by ground reflection. In urban areas with higher reflectivity, UV exposure occurs routinely. To discover the solar UV radiation regulation mechanism of vegetation, the spectral reflectance and transmittance of plant leaves were measured with a spectrophotometer. Typically, higher plants have low leaf reflectance (around 5%) and essentially zero transmittance throughout the UV region regardless of plant species and seasonal change. Accordingly, incident UV radiation decreases to 5% by being reflected and is reduced to zero by passing through a leaf. Therefore, stratified structures of vegetation are working as another terminator of UV rays, protecting whole terrestrial ecosystems, while vegetation at waterfronts contributes to protect aquatic ecosystems. It is possible to protect the human population from harmful UV radiation by urban landscape design of tree shade and the botanical environment. Even thin but uniformly distributed canopy is effective in attenuating UV radiation. To intercept diffuse radiation, UV screening by vertical structures such as hedges should be considered. Reflectivity of vegetation is around 2%, as foliage surfaces reduce incident UV radiation via reflection, while also eliminating it by transmittance. Accordingly, vegetation reduces incident UV radiation to around 2% by reflection. Vegetation influence on ambient UV radiation is broad-spectrum throughout the UV region. Only trees provide cool UV protective shade. Urban landscapes aimed at abating urban heat islands integrated with a reduction of human UV over-exposure would contribute to mitigation of climate change.

  2. Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor

    Science.gov (United States)

    Kim, Yunjeong; Liu, Hongwei; Galasiti Kankanamalage, Anushka C.; Weerasekara, Sahani; Hua, Duy H.; Groutas, William C.; Chang, Kyeong-Ok; Pedersen, Niels C.

    2016-01-01

    Coronaviruses infect animals and humans causing a wide range of diseases. The diversity of coronaviruses in many mammalian species is contributed by relatively high mutation and recombination rates during replication. This dynamic nature of coronaviruses may facilitate cross-species transmission and shifts in tissue or cell tropism in a host, resulting in substantial change in virulence. Feline enteric coronavirus (FECV) causes inapparent or mild enteritis in cats, but a highly fatal disease, called feline infectious peritonitis (FIP), can arise through mutation of FECV to FIP virus (FIPV). The pathogenesis of FIP is intimately associated with immune responses and involves depletion of T cells, features shared by some other coronaviruses like Severe Acute Respiratory Syndrome Coronavirus. The increasing risks of highly virulent coronavirus infections in humans or animals call for effective antiviral drugs, but no such measures are yet available. Previously, we have reported the inhibitors that target 3C-like protease (3CLpro) with broad-spectrum activity against important human and animal coronaviruses. Here, we evaluated the therapeutic efficacy of our 3CLpro inhibitor in laboratory cats with FIP. Experimental FIP is 100% fatal once certain clinical and laboratory signs become apparent. We found that antiviral treatment led to full recovery of cats when treatment was started at a stage of disease that would be otherwise fatal if left untreated. Antiviral treatment was associated with a rapid improvement in fever, ascites, lymphopenia and gross signs of illness and cats returned to normal health within 20 days or less of treatment. Significant reduction in viral titers was also observed in cats. These results indicate that continuous virus replication is required for progression of immune-mediated inflammatory disease of FIP. These findings may provide important insights into devising therapeutic strategies and selection of antiviral compounds for further

  3. Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor.

    Directory of Open Access Journals (Sweden)

    Yunjeong Kim

    2016-03-01

    Full Text Available Coronaviruses infect animals and humans causing a wide range of diseases. The diversity of coronaviruses in many mammalian species is contributed by relatively high mutation and recombination rates during replication. This dynamic nature of coronaviruses may facilitate cross-species transmission and shifts in tissue or cell tropism in a host, resulting in substantial change in virulence. Feline enteric coronavirus (FECV causes inapparent or mild enteritis in cats, but a highly fatal disease, called feline infectious peritonitis (FIP, can arise through mutation of FECV to FIP virus (FIPV. The pathogenesis of FIP is intimately associated with immune responses and involves depletion of T cells, features shared by some other coronaviruses like Severe Acute Respiratory Syndrome Coronavirus. The increasing risks of highly virulent coronavirus infections in humans or animals call for effective antiviral drugs, but no such measures are yet available. Previously, we have reported the inhibitors that target 3C-like protease (3CLpro with broad-spectrum activity against important human and animal coronaviruses. Here, we evaluated the therapeutic efficacy of our 3CLpro inhibitor in laboratory cats with FIP. Experimental FIP is 100% fatal once certain clinical and laboratory signs become apparent. We found that antiviral treatment led to full recovery of cats when treatment was started at a stage of disease that would be otherwise fatal if left untreated. Antiviral treatment was associated with a rapid improvement in fever, ascites, lymphopenia and gross signs of illness and cats returned to normal health within 20 days or less of treatment. Significant reduction in viral titers was also observed in cats. These results indicate that continuous virus replication is required for progression of immune-mediated inflammatory disease of FIP. These findings may provide important insights into devising therapeutic strategies and selection of antiviral compounds for

  4. Antifungal combinations.

    Science.gov (United States)

    Vitale, Roxana G; Afeltra, Javier; Dannaoui, Eric

    2005-01-01

    The increase in fungal infections and the change in fungal epidemiology is caused by the extensive use of antifungal agents to treat fungal infections that are being diagnosed in severly immunocompromised hosts. In addition, opportunistic fungal infections resistant to antifungal drugs have become increasingly common, and the armamentarium for treatment remains limited. A possible approach to overcoming these problems is to combine antifungal drugs, especially if the mechanisms of action are different. The in vitro test is the first step to evaluate possible antifungal combinations. In this chapter, the three most frequently used metholodologies are described: checkerboard, E-test, and time-kill curves. The description of each technique and intrepretaion of the results are addressed in detail.

  5. Newly isolated Paenibacillus tyrfis sp. nov., from Malaysian tropical peat swamp soil with broad spectrum antimicrobial activity

    Directory of Open Access Journals (Sweden)

    Yoong Kit eAw

    2016-03-01

    Full Text Available Emergence of antimicrobial resistance coupled with the slowdown in discovery of new antimicrobial compounds points to serious consequences in human health. Therefore, scientists are looking for new antimicrobial compounds from unique and understudied ecosystem such as tropical peat swamp forests. Over the course of isolating antimicrobial producing bacteria from North Selangor tropical peat swamp forest, Malaysia, a Gram variable, rod shaped, endospore forming, facultative anaerobic novel strain MSt1T that exerts potent and broad spectrum antimicrobial activity was isolated. Phylogenetic analysis using 16S rRNA gene sequences showed that strain MSt1T belonged to the genus Paenibacillus with the highest similarity with Paenibacillus elgii SD17T (99.5%. Whole genome comparison between strain MSt1T with its closely related species using average nucleotide identity (ANI revealed that similarity between strain MSt1T with Paenibacillus elgii B69 (93.45% and Paenibacillus ehimensis A2 (90.42% was below the recommended threshold of 95%. Further analysis using in silico pairwise DDH also showed that similarity between strain MSt1T with P. elgii B69 (55.4% and P. ehimensis A2 (43.7% was below the recommended threshold of 70%. Strain MSt1T contained meso-diaminopilemic acid in the cell wall and MK-7 as the major menaquinone. The major fatty acids of strain MSt1T were anteiso-C15:0 (48.2% and C16:0 (29.0% whereas the polar lipid profile consisted of phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, one unknown lipid, two unknown glycolipids and one unknown phospholipid. Total DNA G+C content of strain MSt1T was 51.5 mol%. Extract from strain MSt1T exerted strong antimicrobial activity against Escherichia coli ATCC 25922 (MIC = 1.5 µg/mL, MRSA ATCC 700699 (MIC = 25 µg/mL and Candida albicans IMR (MIC = 12.5 µg/mL. Partially purified active fraction exerted strong effect against Escherichia coli ATCC 25922 resulting in cell rupture

  6. Antimicrobial activity of cathelicidins BMAP28, SMAP28, SMAP29, and PMAP23 against Pasteurella multocida is more broad-spectrum than host species specific.

    Science.gov (United States)

    Brogden, Kim A; Nordholm, Gwen; Ackermann, Mark

    2007-01-17

    The antimicrobial activity of linear, cationic alpha-helical peptides from cattle (BMAP28), sheep (SMAP28 and SMAP29), and pigs (PMAP23) were assessed to determine if activity was selective for Pasteurella multocida from a particular animal species or broad-spectrum against all P. multocida tested. The antimicrobial activities of synthetic peptides were determined for P. multocida isolated from cattle (10 isolates), sheep (10 isolates), and pigs (10 isolates) in a broth microdilution assay. All thirty isolates of P. multocida were susceptible to BMAP28 (MICs and MBCs, 1.0-1.9 microM); SMAP28 and SMAP29 (MICs and MBCs, 0.2-0.7 microM); and PMAP23 (MICs and MBCs, 4.3 to > or = 6.8 microM). Overall, the results of this study suggest that synthesized cathelicidins from cattle, sheep, and pigs had broad-spectrum antimicrobial activity against all P. multocida.

  7. Proteasome Accessory Factor C (pafC) Is a novel gene Involved in Mycobacterium Intrinsic Resistance to broad-spectrum antibiotics - Fluoroquinolones

    OpenAIRE

    Qiming Li; Longxiang Xie; Quanxin Long; Jinxiao Mao; Hui Li; Mingliang Zhou; Jianping Xie

    2015-01-01

    Antibiotics resistance poses catastrophic threat to global public health. Novel insights into the underlying mechanisms of action will inspire better measures to control drug resistance. Fluoroquinolones are potent and widely prescribed broad-spectrum antibiotics. Bacterial protein degradation pathways represent novel druggable target for the development of new classes of antibiotics. Mycobacteria proteasome accessory factor C (pafC), a component of bacterial proteasome, is involved in fluoro...

  8. Rice RING protein OSBBI1 with E3 ligase activity confers broad-spectrum resistance against Magnaporthe oryzae by modifying the cell wall defence

    Institute of Scientific and Technical Information of China (English)

    Wei Li; Zuhua He; Sihui Zhong; Guojun Li; Qun Li; Bizeng Mao; Yiwen Deng; Huijuan Zhang; Longjun Zeng; Fengming Song

    2011-01-01

    Emerging evidence suggests that E3 ligases play critical roles in diverse biological processes, including innate immune responses in plants. However, the mechanism of the E3 ligase involvement in plant innate immunity is unclear.We report that a rice gene, OsBBI1, encoding a RING finger protein with E3 ligase activity, mediates broad-spectrum disease resistance. The expression of OSBBI1 was induced by rice blast fungus Magnaporthe oryzae, as well as chemical inducers, benzothiadiazole and salicylic acid. Biochemical analysis revealed that OsBBI1 protein possesses E3ubiquitin ligase activity in vitro. Genetic analysis revealed that the loss of OsBBI1 function in a Tos17-insertion line increased susceptibility, while the overexpression of OsBBI1 in transgenic plants conferred enhanced resistance to multiple races of M.oryzae. This indicates that OsBBI1 modulates broad-spectrum resistance against the blast fungus. The OsBBII-overexpressing plants showed higher levels of H,O, accumulation in cells and higher levels of phenolic compounds and cross-linking of proteins in cell walls at infection sites by M. Oryzae compared with wild-type(WT)plants. The cell walls were thicker in the OsBB11-overexpressing plants and thinner in the mutant plants than in the WT plants. Our results suggest that OsBBH modulates broad-spectrum resistance to blast fungus by modifying cell wall defence responses. The functional characterization of OsBBI1 provides insight into the E3 ligase-mediated innate immunity, and a practical tool for constructing broad-spectrum resistance against the most destructive disease in rice.

  9. 关于广谱哲学的交叉性学科特点%The Features of Interdiscipline of Broad-spectrum Philosophy

    Institute of Scientific and Technical Information of China (English)

    苏淼

    2016-01-01

    Broad-spectrum philosophy is a new type of philosophy, which inosculates Marxist philosophy, system science and modern mathematics as a whole, with a laterally interdisciplinary characteristic. It has the important theoretical significance to study laterally interdisciplinary mechanism, functions and characteristics of broad-spectrum philosophy, because it can help to understand the broad-spectrum philosophy and understand the nature of common lateral interdiscipline.%广谱哲学是融马克思主义哲学、系统科学和现代数学为一体的新型哲学门派,具有跨领域性、跨学科性的横断交叉学科的特点。研究广谱哲学横断交叉的机制、作用和特点,对于人们了解广谱哲学,了解一般的横断交叉学科的性质,具有重要的理论意义。

  10. Leveraging the attributes of Mucor hiemalis-derived silver nanoparticles for a synergistic broad-spectrum antimicrobial platform

    Directory of Open Access Journals (Sweden)

    Nafe Aziz

    2016-12-01

    Full Text Available Driven by the need to engineer robust surface coatings for medical devices to prevent infection and sepsis, incorporation of nanoparticles has surfaced as a promising avenue to enhance non-fouling efficacy. Microbial synthesis of such nanoscale metallic structures is of substantive interest as this can offer an eco-friendly, cost-effective and sustainable route for further development. Here we present a Mucor hiemalis-derived fungal route for synthesis of silver nanoparticles, which display significant antimicrobial properties when tested against six pathological bacterial strains (Klebsiella pneumonia, Pseudomonas brassicacearum, Aeromonas hydrophila, Escherichia coli, Bacillus cereus and Staphylococcus aureus and three pathological fungal strains (Candida albicans, oxysporum, and Aspergillus flavus. These antimicrobial attributes were comparable to those of established antibiotics (streptomycin, tetracycline, kanamycin and rifampicin and fungicides (amphotericin B, fluconazole and ketoconazole, respectively. Importantly, these nanoparticles show significant synergistic characteristics when combined with the antibiotics and fungicides to offer substantially greater resistance to microbial growth. The blend of antibacterial and antifungal properties, coupled with their intrinsic green and facile synthesis, makes these biogenic nanoparticles particularly attractive for future applications in nanomedicine ranging from topical ointments and bandages for wound healing to coated stents.

  11. Leveraging the Attributes of Mucor hiemalis-Derived Silver Nanoparticles for a Synergistic Broad-Spectrum Antimicrobial Platform

    Science.gov (United States)

    Aziz, Nafe; Pandey, Rishikesh; Barman, Ishan; Prasad, Ram

    2016-01-01

    Driven by the need to engineer robust surface coatings for medical devices to prevent infection and sepsis, incorporation of nanoparticles has surfaced as a promising avenue to enhance non-fouling efficacy. Microbial synthesis of such nanoscale metallic structures is of substantive interest as this can offer an eco-friendly, cost-effective, and sustainable route for further development. Here we present a Mucor hiemalis-derived fungal route for synthesis of silver nanoparticles, which display significant antimicrobial properties when tested against six pathological bacterial strains (Klebsiella pneumoniae, Pseudomonas brassicacearum, Aeromonas hydrophila, Escherichia coli, Bacillus cereus, and Staphylococcus aureus) and three pathological fungal strains (Candida albicans, Fusarium oxysporum, and Aspergillus flavus). These antimicrobial attributes were comparable to those of established antibiotics (streptomycin, tetracycline, kanamycin, and rifampicin) and fungicides (amphotericin B, fluconazole, and ketoconazole), respectively. Importantly, these nanoparticles show significant synergistic characteristics when combined with the antibiotics and fungicides to offer substantially greater resistance to microbial growth. The blend of antibacterial and antifungal properties, coupled with their intrinsic “green” and facile synthesis, makes these biogenic nanoparticles particularly attractive for future applications in nanomedicine ranging from topical ointments and bandages for wound healing to coated stents. PMID:28018316

  12. Targeting N-Glycan Cryptic Sugar Moieties for Broad-Spectrum Virus Neutralization: Progress in Identifying Conserved Molecular Targets in Viruses of Distinct Phylogenetic Origins

    Directory of Open Access Journals (Sweden)

    Denong Wang

    2015-03-01

    Full Text Available Identifying molecular targets for eliciting broadly virus-neutralizing antibodies is one of the key steps toward development of vaccines against emerging viral pathogens. Owing to genomic and somatic diversities among viral species, identifying protein targets for broad-spectrum virus neutralization is highly challenging even for the same virus, such as HIV-1. However, viruses rely on host glycosylation machineries to synthesize and express glycans and, thereby, may display common carbohydrate moieties. Thus, exploring glycan-binding profiles of broad-spectrum virus-neutralizing agents may provide key information to uncover the carbohydrate-based virus-neutralizing epitopes. In this study, we characterized two broadly HIV-neutralizing agents, human monoclonal antibody 2G12 and Galanthus nivalis lectin (GNA, for their viral targeting activities. Although these agents were known to be specific for oligomannosyl antigens, they differ strikingly in virus-binding activities. The former is HIV-1 specific; the latter is broadly reactive and is able to neutralize viruses of distinct phylogenetic origins, such as HIV-1, severe acute respiratory syndrome coronavirus (SARS-CoV, and human cytomegalovirus (HCMV. In carbohydrate microarray analyses, we explored the molecular basis underlying the striking differences in the spectrum of anti-virus activities of the two probes. Unlike 2G12, which is strictly specific for the high-density Man9GlcNAc2Asn (Man9-clusters, GNA recognizes a number of N-glycan cryptic sugar moieties. These include not only the known oligomannosyl antigens but also previously unrecognized tri-antennary or multi-valent GlcNAc-terminating N-glycan epitopes (Tri/m-Gn. These findings highlight the potential of N-glycan cryptic sugar moieties as conserved targets for broad-spectrum virus neutralization and suggest the GNA-model of glycan-binding warrants focused investigation.

  13. Tricyclic GyrB/ParE (TriBE inhibitors: a new class of broad-spectrum dual-targeting antibacterial agents.

    Directory of Open Access Journals (Sweden)

    Leslie W Tari

    Full Text Available Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB and topoisomerase IV (ParE have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD, we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.

  14. Extreme Longevity in Proteinaceous Deep-Sea Corals

    Energy Technology Data Exchange (ETDEWEB)

    Roark, E B; Guilderson, T P; Dunbar, R B; Fallon, S J; Mucciarone, D A

    2009-02-09

    Deep-sea corals are found on hard substrates on seamounts and continental margins world-wide at depths of 300 to {approx}3000 meters. Deep-sea coral communities are hotspots of deep ocean biomass and biodiversity, providing critical habitat for fish and invertebrates. Newly applied radiocarbon age date from the deep water proteinaceous corals Gerardia sp. and Leiopathes glaberrima show that radial growth rates are as low as 4 to 35 {micro}m yr{sup -1} and that individual colony longevities are on the order of thousands of years. The management and conservation of deep sea coral communities is challenged by their commercial harvest for the jewelry trade and damage caused by deep water fishing practices. In light of their unusual longevity, a better understanding of deep sea coral ecology and their interrelationships with associated benthic communities is needed to inform coherent international conservation strategies for these important deep-sea ecosystems.

  15. Broad-spectrum inhibition of HIV-1 by a monoclonal antibody directed against a gp120-induced epitope of CD4.

    Directory of Open Access Journals (Sweden)

    Samuele E Burastero

    Full Text Available To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1.

  16. The broad-spectrum antiviral compound ST-669 restricts chlamydial inclusion development and bacterial growth and localizes to host cell lipid droplets within treated cells.

    Science.gov (United States)

    Sandoz, Kelsi M; Valiant, William G; Eriksen, Steven G; Hruby, Dennis E; Allen, Robert D; Rockey, Daniel D

    2014-07-01

    Novel broad-spectrum antimicrobials are a critical component of a strategy for combating antibiotic-resistant pathogens. In this study, we explored the activity of the broad-spectrum antiviral compound ST-669 for activity against different intracellular bacteria and began a characterization of its mechanism of antimicrobial action. ST-669 inhibits the growth of three different species of chlamydia and the intracellular bacterium Coxiella burnetii in Vero and HeLa cells but not in McCoy (murine) cells. The antichlamydial and anti-C. burnetii activity spectrum was consistent with those observed for tested viruses, suggesting a common mechanism of action. Cycloheximide treatment in the presence of ST-669 abrogated the inhibitory effect, demonstrating that eukaryotic protein synthesis is required for tested activity. Immunofluorescence microscopy demonstrated that different chlamydiae grow atypically in the presence of ST-669, in a manner that suggests the compound affects inclusion formation and organization. Microscopic analysis of cells treated with a fluorescent derivative of ST-669 demonstrated that the compound localized to host cell lipid droplets but not to other organelles or the host cytosol. These results demonstrate that ST-669 affects intracellular growth in a host-cell-dependent manner and interrupts proper development of chlamydial inclusions, possibly through a lipid droplet-dependent process.

  17. Comparison of measured parameters from a 24-keV and a broad spectrum epithermal neutron beam for neutron capture therapy: an identification of consequential parameters.

    Science.gov (United States)

    Fairchild, R G; Saraf, S K; Kalef-Ezra, J; Laster, B H

    1990-01-01

    Epithermal neutron beams are under development in a number of locations in the U.S. and abroad. The increased penetration in tissue provided by these neurons should circumvent problems associated with the rapid attenuation of thermal neutron beams encountered in previous clinical trials of neutron capture therapy (NCT). Physical and radiobiological experiments with two "intermediate energy" or "epithermal" beams have been reported. A comparison is made here between the 24-keV iron-filtered beam at Harwell, England, and the broad-spectrum Al2 O3 moderated beam at the Brookhaven Medical Research Reactor (BMRR). In addition, parameters which are relevant for NCT, and which are best suited for evaluation and comparison of beams, are discussed. Particular attention is paid to the mean neutron energy which can be tolerated without significant reduction of therapeutic gain (TG), where TG is the ratio of tumor dose to maximum normal tissue dose. It is suggested that the simplest and most meaningful parameters for comparison of beam intensity and purity are the epithermal neutron fluence rate, and the fast neutron dose per epithermal neutron (4.2 X 10(-11) rad/neutron for the broad-spectrum beam and 29 X 10(-11) rad/neutron for the 24-keV beam). While the Al2O3 beam is close to optimal, the 24-keV beam produces a significant fast neutron dose which results in a lower TG.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Sucrose-mediated priming of plant defense responses and broad-spectrum disease resistance by overexpression of the maize pathogenesis-related PRms protein in rice plants.

    Science.gov (United States)

    Gómez-Ariza, Jorge; Campo, Sonia; Rufat, Mar; Estopà, Montserrat; Messeguer, Joaquima; San Segundo, Blanca; Coca, María

    2007-07-01

    Expression of pathogenesis-related (PR) genes is part of the plant's natural defense response against pathogen attack. The PRms gene encodes a fungal-inducible PR protein from maize. Here, we demonstrate that expression of PRms in transgenic rice confers broad-spectrum protection against pathogens, including fungal (Magnaporthe oryzae, Fusarium verticillioides, and Helminthosporium oryzae) and bacterial (Erwinia chrysanthemi) pathogens. The PRms-mediated disease resistance in rice plants is associated with an enhanced capacity to express and activate the natural plant defense mechanisms. Thus, PRms rice plants display a basal level of expression of endogenous defense genes in the absence of the pathogen. PRms plants also exhibit stronger and quicker defense responses during pathogen infection. We also have found that sucrose accumulates at higher levels in leaves of PRms plants. Sucrose responsiveness of rice defense genes correlates with the pathogen-responsive priming of their expression in PRms rice plants. Moreover, pretreatment of rice plants with sucrose enhances resistance to M. oryzae infection. Together, these results support a sucrose-mediated priming of defense responses in PRms rice plants which results in broad-spectrum disease resistance.

  19. IPC synthase as a useful target for antifungal drugs.

    Science.gov (United States)

    Sugimoto, Yuichi; Sakoh, Hiroki; Yamada, Koji

    2004-12-01

    Inositol phosphorylceramide (IPC) synthase is a common and essential enzyme in fungi and plants, which catalyzes the transfer of phosphoinositol to the C-1 hydroxy of ceramide to produce IPC. This reaction is a key step in fungal sphingolipid biosynthesis, therefore the enzyme is a potential target for the development of nontoxic therapeutic antifungal agents. Natural products with a desired biological activity, aureobasidin A (AbA), khafrefungin, and galbonolide A, have been reported. AbA, a cyclic depsipeptide containing 8 amino acids and a hydroxyl acid, is a broad spectrum antifungal with strong activity against many pathogenic fungi such as Candida spp., Cryptococcus neoformans, and some Aspergillus spp. Khafrefungin, an aldonic acid ester with a C22 long alkyl chain, has antifungal activity against C. albicans, Cr. Neoformans, and Saccharomyces cerevisiae. Galbonolide A is a 14-membered macrolide with fungicidal activity against clinically important strains, and is especially potent against Cr. neoformans. These classes of natural products are potent and specific antifungal agents. We review current progress in the development of IPC synthase inhibitors with antifungal activities, and present structure-activity relationships (SAR), physicochemical and structural properties, and synthetic methodology for chemical modification.

  20. THE IMPACT OF ANTIFUNGALS ON TOLL-LIKE RECEPTORS

    Directory of Open Access Journals (Sweden)

    Mircea Radu Mihu

    2014-03-01

    Full Text Available Fungi are increasingly recognized as major pathogens in immunocompromised individuals. The most common invasive fungal infections are caused by Candida spp., Aspergillus spp. and Cryptococcus spp. Amphotericin B has remained the cornerstone of therapy against many fulminant fungal infections but its use is limited by its multitude of side effects. Echinocandins are a newer class of antifungal drugs with activity against Candida spp. and Aspergillus spp. and constitutes an alternative to amphotericin B due to superior patient tolerability and fewer side effects. Due to their excellent bioavailability and oral availability, azoles continue to be heavily used for simple, such as fluconazole for candidal vaginitis, and complex diseases, such as voriconazole for aspergilloisis. The objective of this paper is to present current knowledge regarding the multiple interactions between the broad spectrum antifungals and the innate immune response, primarily focusing on the toll-like receptors.

  1. Synthesis of heterocycle-attached methylidenebenzenesulfonohydrazones as antifungal agents.

    Science.gov (United States)

    Gao, Zhinan; Lv, Min; Li, Qin; Xu, Hui

    2015-11-15

    A series of heterocycle-attached methylidenebenzenesulfonohydrazone derivatives were synthesized and evaluated for their antifungal activities against seven phytopathogenic fungi such as Fusarium graminearum, Alternaria solani, Valsa mali, Phytophthora capsici, Fusarium solani, Botrytis cinerea, and Glomerella cingulata. Compounds 7b, 8d, 9a, 9b and 9d exhibited a good and broad-spectrum of antifungal activities against at least five phytopathogenic fungi at the concentration of 100 μg/mL. It demonstrated that addition of one double bond between the phenylsulfonylhydrazone fragment and the furan ring of 6a,b,d could afford more active compounds 9a,b,d; however, introduction of the nitro group on the phenyl ring of 6a-9a gave less potent compounds 6e-9e. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Antifungal amphiphilic aminoglycoside K20: bioactivities and mechanism of action

    Directory of Open Access Journals (Sweden)

    Sanjib K. Shrestha

    2014-12-01

    Full Text Available K20 is a novel amphiphilic antifungal aminoglycoside that is synthetically derived from the antibiotic kanamycin A. Reported here are investigations of K20’s antimicrobial activities, cytotoxicity, and fungicidal mechanism of action. In vitro growth inhibitory activities against a variety of human and plant pathogenic yeasts, filamentous fungi, and bacteria were determined using microbroth dilution assays and time-kill curve analyses, and hemolytic and animal cell cytotoxic activities were determined. Effects on Cryptococcus neoformans H-99 infectivity were determined with a preventive murine lung infection model. The antifungal mechanism of action was studied using intact fungal cells, yeast lipid mutants, and small unilamellar lipid vesicles. K20 exhibited broad-spectrum in vitro antifungal activities but not antibacterial activities. Pulmonary, single dose-administration of K20 reduced C. neoformans lung infection rates 4-fold compared to controls. Hemolysis and half-maximal cytotoxicities of mammalian cells occurred at concentrations that were 10 to 32-fold higher than fungicidal MICs. With fluorescein isothiocyanate, 20 to 25 mg/L K20 caused staining of >95% of C. neoformans and Fusarium graminearum cells and at 31.3 mg/L caused rapid leakage (30 to 80% in 15 min of calcein from preloaded small unilamellar lipid vesicles. K20 appears to be a broad-spectrum fungicide, capable of reducing the infectivity of C. neoformans, and exhibits low hemolytic activity and mammalian cell toxicity. It perturbs the plasma membrane by mechanisms that are lipid modulated. K20 is a novel amphiphilic aminoglycoside amenable to scalable production and a potential lead antifungal for therapeutic and crop protection applications.

  3. 网格蛋白介导型内吞作用与广谱抗病毒药%Clathrin-mediated endocytosis and broad-spectrum antivirals

    Institute of Scientific and Technical Information of China (English)

    周丽; 杨晓虹; 徐利保; 肖军海

    2013-01-01

    Viral disease is a serious threat for human health. Alhough plenty of antiviral agents have been used in clinical treatment, many viruses are resistant to them via virus mutation. And novel harmful viruses emerge in endlessly. So research and development of new antiviral drugs, especially the agents that are of broad-spectrum antiviral activity is particularly important. Clathrin-mediated endocytosis is the most common pathway used by viruses and pathogens for entering host cells. The inhibitors of clathrin-me-diated endocytosis may block the entry of viruses and pathogens, thus prevent viral infection. For the inhibitors do not directly act on the virus itself, it is hard to induce virus mutations which produce drug resistance. Clathrin-mediated endocytosis is the potential target of broad-spectrum antiviral agents in recent years. This review focuses on the mechanism of virus entry through clathrin-mediated endocytosis, the recent advances of clathrin-mediated endocytosis inhibitors and their potential applications in broad-spectrum antiviral therapeutics field.%病毒性疾病对人类的健康造成了巨大的威胁,虽然有很多药物用于临床治疗,但由于病毒的易变异性,对现有的抗病毒药物极易产生耐药性,而新发病毒又层出不穷,因此研发新的抗病毒药物尤其是广谱且不易产生耐药的抗病毒药物对于病毒性疾病的治疗就显得尤为重要.网格蛋白介导型内吞是许多病毒和病原体进入宿主细胞的主要途径,抑制此途径可阻断病毒进入宿主细胞,从而抑制病毒感染,由于其功能和机制与病毒自身无关,不易产生耐药,是近年来广谱抗病毒药物的潜在作用靶标.本文结合国内外最新研究报道,简要综述了病毒依赖网格蛋白介导型内吞入胞的机制,网格蛋白介导型内吞抑制剂的研究现状,及其在广谱抗病毒药物研发中的潜在应用前景.

  4. Proteasome Accessory Factor C (pafC) Is a novel gene Involved in Mycobacterium Intrinsic Resistance to broad-spectrum antibiotics--Fluoroquinolones.

    Science.gov (United States)

    Li, Qiming; Xie, Longxiang; Long, Quanxin; Mao, Jinxiao; Li, Hui; Zhou, Mingliang; Xie, Jianping

    2015-07-03

    Antibiotics resistance poses catastrophic threat to global public health. Novel insights into the underlying mechanisms of action will inspire better measures to control drug resistance. Fluoroquinolones are potent and widely prescribed broad-spectrum antibiotics. Bacterial protein degradation pathways represent novel druggable target for the development of new classes of antibiotics. Mycobacteria proteasome accessory factor C (pafC), a component of bacterial proteasome, is involved in fluoroquinolones resistance. PafC deletion mutants are hypersensitive to fluoroquinolones, including moxifloxacin, norfloxacin, ofloxacin, ciprofloxacin, but not to other antibiotics such as isoniazid, rifampicin, spectinomycin, chloramphenicol, capreomycin. This phenotype can be restored by complementation. The pafC mutant is hypersensitive to H2O2 exposure. The iron chelator (bipyridyl) and a hydroxyl radical scavenger (thiourea) can abolish the difference. The finding that pafC is a novel intrinsic selective resistance gene provided new evidence for the bacterial protein degradation pathway as druggable target for the development of new class of antibiotics.

  5. Novel, broad-spectrum anticonvulsants containing a sulfamide group: advancement of N-((benzo[b]thien-3-yl)methyl)sulfamide (JNJ-26990990) into human clinical studies.

    Science.gov (United States)

    Parker, Michael H; Smith-Swintosky, Virginia L; McComsey, David F; Huang, Yifang; Brenneman, Douglas; Klein, Brian; Malatynska, Ewa; White, H Steve; Milewski, Michael E; Herb, Mark; Finley, Michael F A; Liu, Yi; Lubin, Mary Lou; Qin, Ning; Iannucci, Robert; Leclercq, Laurent; Cuyckens, Filip; Reitz, Allen B; Maryanoff, Bruce E

    2009-12-10

    In seeking broad-spectrum anticonvulsants to treat epilepsy and other neurological disorders, we synthesized and tested a group of sulfamide derivatives (4a-k, 5), which led to the clinical development of 4a (JNJ-26990990). This compound exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures, with very weak inhibition of human carbonic anhydrase-II (IC(50) = 110 microM). The pharmacological profile for 4a supports its potential in the treatment of multiple forms of epilepsy, including pharmacoresistant variants. Mechanistically, 4a inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels but was not effective as a K(+) channel opener. The pharmacokinetics and metabolic properties of 4a are discussed.

  6. Bio-Inspired Wide-Angle Broad-Spectrum Cylindrical Lens Based on Reflections from Micro-Mirror Array on a Cylindrical Elastomeric Membrane

    Directory of Open Access Journals (Sweden)

    Chi-Chieh Huang

    2014-06-01

    Full Text Available We present a wide-angle, broad-spectrum cylindrical lens based on reflections from an array of three-dimensional, high-aspect-ratio micro-mirrors fabricated on a cylindrical elastomeric substrate, functionally inspired by natural reflecting superposition compound eyes. Our device can perform one-dimensional focusing and beam-shaping comparable to conventional refraction-based cylindrical lenses, while avoiding chromatic aberration. The focal length of our cylindrical lens is 1.035 mm, suitable for micro-optical systems. Moreover, it demonstrates a wide field of view of 152° without distortion, as well as modest spherical aberrations. Our work could be applied to diverse applications including laser diode collimation, barcode scanning, holography, digital projection display, microlens arrays, and optical microscopy.

  7. Facile synthesis of Fe3O4 nanoparticles decorated on 3D graphene aerogels as broad-spectrum sorbents for water treatment

    Science.gov (United States)

    Li, Yong; Zhang, Ruofang; Tian, Xike; Yang, Chao; Zhou, Zhaoxin

    2016-04-01

    In order to develop efficient and environment benign sorbents for water purification, the macroscopic multifunctional magnetite-reduced graphene oxides aerogels (M-RGOs) with strong interconnected networks were prepared via a one pot solvothermal method of graphene oxide sheets adsorbing iron ions and in situ simultaneous deposition of Fe3O4 nanoparticles in ethylene glycol or triethylene glycol solvents. Such M-RGOs exhibited excellent sorption capacity to different contaminants, including oils, organic solvents, arsenite ions, as well as dyes. In addition, it was demonstrated that the M-RGOs could be used as column packing materials to manufacture column for water purification by filtration. The method proposed was proved to be versatile to induce synergistic assembly of RGO sheets with other functional metal oxides nanoparticles and as a kind of broad-spectrum sorbents for removing different types of contaminants in water purification, simultaneously.

  8. Transgenic Brassica rapa plants over-expressing eIF(iso)4E variants show broad-spectrum Turnip mosaic virus (TuMV) resistance.

    Science.gov (United States)

    Kim, Jinhee; Kang, Won-Hee; Hwang, Jeena; Yang, Hee-Bum; Dosun, Kim; Oh, Chang-Sik; Kang, Byoung-Cheorl

    2014-08-01

    The protein-protein interaction between VPg (viral protein genome-linked) of potyviruses and eIF4E (eukaryotic initiation factor 4E) or eIF(iso)4E of their host plants is a critical step in determining viral virulence. In this study, we evaluated the approach of engineering broad-spectrum resistance in Chinese cabbage (Brassica rapa) to Turnip mosaic virus (TuMV), which is one of the most important potyviruses, by a systematic knowledge-based approach to interrupt the interaction between TuMV VPg and B. rapa eIF(iso)4E. The seven amino acids in the cap-binding pocket of eIF(iso)4E were selected on the basis of other previous results and comparison of protein models of cap-binding pockets, and mutated. Yeast two-hybrid assay and co-immunoprecipitation analysis demonstrated that W95L, K150L and W95L/K150E amino acid mutations of B. rapa eIF(iso)4E interrupted its interaction with TuMV VPg. All eIF(iso)4E mutants were able to complement an eIF4E-knockout yeast strain, indicating that the mutated eIF(iso)4E proteins retained their function as a translational initiation factor. To determine whether these mutations could confer resistance, eIF(iso)4E W95L, W95L/K150E and eIF(iso)4E wild-type were over-expressed in a susceptible Chinese cabbage cultivar. Evaluation of the TuMV resistance of T1 and T2 transformants demonstrated that the over-expression of the eIF(iso)4E mutant forms can confer resistance to multiple TuMV strains. These data demonstrate the utility of knowledge-based approaches for the engineering of broad-spectrum resistance in Chinese cabbage.

  9. CaLecRK-S.5, a pepper L-type lectin receptor kinase gene, confers broad-spectrum resistance by activating priming

    Science.gov (United States)

    Woo, Joo Yong; Jeong, Kwang Ju; Kim, Young Jin; Paek, Kyung-Hee

    2016-01-01

    In Arabidopsis, several L-type lectin receptor kinases (LecRKs) have been identified as putative immune receptors. However, to date, there have been few analyses of LecRKs in crop plants. Virus-induced gene silencing of CaLecRK-S.5 verified the role of CaLecRK-S.5 in broad-spectrum resistance. Compared with control plants, CaLecRK-S.5-silenced plants showed reduced hypersensitive response, reactive oxygen species burst, secondary metabolite production, mitogen-activated protein kinase activation, and defense-related gene expression in response to Tobacco mosaic virus pathotype P0 (TMV-P0) infection. Suppression of CaLecRK-S.5 expression significantly enhanced the susceptibility to Pepper mild mottle virus pathotype P1,2,3, Xanthomonas campestris pv. vesicatoria, Phytophthora capsici, as well as TMV-P0. Additionally, β-aminobutyric acid treatment and a systemic acquired resistance assay revealed that CaLecRK-S.5 is involved in priming of plant immunity. Pre-treatment with β-aminobutyric acid before viral infection restored the reduced disease resistance phenotypes shown in CaLecRK-S.5-silenced plants. Systemic acquired resistance was also abolished in CaLecRK-S.5-silenced plants. Finally, RNA sequencing analysis indicated that CaLecRK-S.5 positively regulates plant immunity at the transcriptional level. Altogether, these results suggest that CaLecRK-S.5-mediated broad-spectrum resistance is associated with the regulation of priming. PMID:27647723

  10. CaLecRK-S.5, a pepper L-type lectin receptor kinase gene, confers broad-spectrum resistance by activating priming.

    Science.gov (United States)

    Woo, Joo Yong; Jeong, Kwang Ju; Kim, Young Jin; Paek, Kyung-Hee

    2016-10-01

    In Arabidopsis, several L-type lectin receptor kinases (LecRKs) have been identified as putative immune receptors. However, to date, there have been few analyses of LecRKs in crop plants. Virus-induced gene silencing of CaLecRK-S.5 verified the role of CaLecRK-S.5 in broad-spectrum resistance. Compared with control plants, CaLecRK-S.5-silenced plants showed reduced hypersensitive response, reactive oxygen species burst, secondary metabolite production, mitogen-activated protein kinase activation, and defense-related gene expression in response to Tobacco mosaic virus pathotype P0 (TMV-P0) infection. Suppression of CaLecRK-S.5 expression significantly enhanced the susceptibility to Pepper mild mottle virus pathotype P1,2,3, Xanthomonas campestris pv. vesicatoria, Phytophthora capsici, as well as TMV-P0 Additionally, β-aminobutyric acid treatment and a systemic acquired resistance assay revealed that CaLecRK-S.5 is involved in priming of plant immunity. Pre-treatment with β-aminobutyric acid before viral infection restored the reduced disease resistance phenotypes shown in CaLecRK-S.5-silenced plants. Systemic acquired resistance was also abolished in CaLecRK-S.5-silenced plants. Finally, RNA sequencing analysis indicated that CaLecRK-S.5 positively regulates plant immunity at the transcriptional level. Altogether, these results suggest that CaLecRK-S.5-mediated broad-spectrum resistance is associated with the regulation of priming.

  11. Prevalence of broad-spectrum cephalosporin-resistant Escherichia coli isolates in food samples in Tunisia, and characterization of integrons and antimicrobial resistance mechanisms implicated.

    Science.gov (United States)

    Ben Slama, Karim; Jouini, Ahlem; Ben Sallem, Rym; Somalo, Sergio; Sáenz, Yolanda; Estepa, Vanesa; Boudabous, Abdellatif; Torres, Carmen

    2010-02-28

    The presence of broad-spectrum-cephalosporin-resistant Escherichia coli isolates and the implicated mechanisms of resistance were investigated in 79 food samples of animal origin obtained in different supermarkets and local butcheries in Tunisia. Ten of these samples (12.6%) harbored extended-spectrum beta-lactamase (ESBL) producing E. coli isolates and 13 ESBL-positive isolates were recovered (one or two/sample), which exhibited nine different Pulsed-Field-Gel-Electrophoresis (PFGE) patterns. ESBLs detected were the following: CTX-M-1 (10 strains), CTX-M-1+TEM-1b (2 strains) and CTX-M-1+TEM-20 (1 strain). The orf477 sequence was identified downstream of bla(CTX-M-1) gene in all 13 strains and ISEcp1 upstream in 9 strains. All ESBL-positive strains were included into phylogenetic group A or B1 (4 and 9 strains, respectively). Three of the 79 food samples (3.8%) contained broad-spectrum-cephalosporin-resistant and ESBL-negative E. coli isolates with AmpC phenotype. One isolate per sample was studied, and they showed unrelated PFGE patterns. The CMY-2 type beta-lactamase was identified in one of these 3 strains and specific point mutations in the promoter/attenuator region of ampC gene (at positions -42, -18, -1 and +58) were detected in the remaining two strains. Twelve ESBL-positive and one ESBL-negative E. coli strains contained class 1 integrons with the following gene cassette arrangements: dfrA1+aadA (6 strains) and dfrA17+aadA5 (7 strains). E. coli strains from food samples could represent a reservoir of ESBL-encoding genes and integrons that could be transmitted to humans through the food chain.

  12. Characterization of an antifungal compound produced by Bacillus sp. strain A(5) F that inhibits Sclerotinia sclerotiorum.

    Science.gov (United States)

    Kumar, Ankit; Saini, Sandeep; Wray, Victor; Nimtz, Manfred; Prakash, Anil; Johri, B N

    2012-12-01

    A potential antagonist, Bacillus sp. strain A(5) F was isolated from soybean rhizosphere following in vitro dual plate screening. The bacterium displayed strong inhibitory activity in vitro against soybean stem rot pathogen, Sclerotinia sclerotiorum. The culture supernatant of strain A(5) F completely suppressed the mycelial growth of the pathogen, indicating that suppression was due to the presence of antifungal compounds in the culture filtrate. The culture filtrate also suppressed other phytopathogenic fungi including Fusarium oxysporum and Macrophomina phaseolina, in vitro suggesting a broad spectrum antagonistic activity against fungal pathogens. Chemical extraction followed by chromatographic analysis resulted in two antifungal fractions. The high resolution-electron spin ionization-mass spectrometry (HR-ESI-MS) and Nuclear Magnetic Resonance (1D and 2D(1) H) spectra of these antifungal fractions revealed the presence of antifungal compounds, one of which showed similarity to bacillomycin D.

  13. Synthesis and antifungal activity of novel indole-replaced streptochlorin analogues.

    Science.gov (United States)

    Zhang, Ming-Zhi; Jia, Chen-Yang; Gu, Yu-Cheng; Mulholland, Nick; Turner, Sarah; Beattie, David; Zhang, Wei-Hua; Yang, Guang-Fu; Clough, John

    2017-01-27

    Based on examples of the successful applications in drug discovery of bioisosterism, a series of streptochlorin analogues in which indole has been replaced by other heterocycles has been designed and synthesized, as a continuation of our studies aimed at the discovery of novel streptochlorin analogues with improved antifungal activity. Biological testing showed that most of the indole-replaced streptochlorin analogues were inactive, though compound 6f had a broad spectrum of antifungal activity with significant activity against Alternaria solani. The SAR study demonstrated that indole ring is an essential moiety for the antifungal activity of streptochlorin analogues, promoting the idea of indole ring as a framework that might be exploited in the future. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  14. A natural component from Euphorbia humifusa Willd displays novel, broad-spectrum anti-influenza activity by blocking nuclear export of viral ribonucleoprotein

    Energy Technology Data Exchange (ETDEWEB)

    Chang, So Young; Park, Ji Hoon [Respiratory Viruses Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400 (Korea, Republic of); Kim, Young Ho; Kang, Jong Seong [College of Pharmacy, Chungnam National University, Daejeon, 305-764 (Korea, Republic of); Min, Ji-Young, E-mail: jiyoung.min@ip-korea.org [Respiratory Viruses Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400 (Korea, Republic of)

    2016-03-04

    The need to develop anti-influenza drugs with novel antiviral mechanisms is urgent because of the rapid rate of antigenic mutation and the emergence of drug-resistant viruses. We identified a novel anti-influenza molecule by screening 861 plant-derived natural components using a high-throughput image-based assay that measures inhibition of the influenza virus infection. 1,3,4,6-tetra-O-galloyl-β-D-glucopyranoside (TGBG) from Euphorbia humifusa Willd showed broad-spectrum anti-influenza activity against two seasonal influenza A strains, A/California/07/2009 (H1N1) and A/Perth/16/2009 (H3N2), and seasonal influenza B strain B/Florida/04/2006. We investigated the mode of action of TGBG using neuraminidase activity inhibition and time-of-addition assays, which evaluate the viral release and entry steps, respectively. We found that TGBG exhibits a novel antiviral mechanism that differs from the FDA-approved anti-influenza drugs oseltamivir which inhibits viral release, and amantadine which inhibits viral entry. Immunofluorescence assay demonstrated that TGBG significantly inhibits nuclear export of influenza nucleoproteins (NP) during the early stages of infection causing NP to accumulate in the nucleus. In addition, influenza-induced activation of the Akt signaling pathway was suppressed by TGBG in a dose-dependent manner. These data suggest that a putative mode of action of TGBG involves inhibition of viral ribonucleoprotein (vRNP) export from the nucleus to the cytoplasm consequently disrupting the assembly of progeny virions. In summary, TGBG has potential as novel anti-influenza therapeutic with a novel mechanism of action. - Highlights: • The plant-derived natural product TGBG has broad-spectrum antiviral activity against seasonal influenza A and B viruses. • TGBG has a novel anti-viral mechanism of action that from differs from the currently available anti-influenza drugs. • TGBG hinders nuclear export of the influenza virus ribonucleoprotein (v

  15. Selenium biotransformations into proteinaceous forms by foodweb organisms of selenium-laden drainage waters in California.

    Science.gov (United States)

    Fan, Teresa W-M; Teh, Swee J; Hinton, David E; Higashi, Richard M

    2002-04-01

    Selenium contamination represents one of the few clear cases where environmental pollution has led to devastation of wildlife populations, most notably in agricultural drainage evaporation and power plant coal-fly ash receiving ponds. Complex biogeochemistry, in particular extensive biotransformations and foodchain transfer, governs Se ecotoxicology and toxicology, for which the mechanism(s) are still elusive. However, total waterborne Se concentration has been widely used as a criterion for regulating and mitigating Se risk in aquatic ecosystems, which does not account for Se biogeochemistry and its site-dependence. There is a need for more reliable indicator(s) that encompass Se ecotoxicity and/or toxicity. Selenomethionine warrants special attention since it simulates Se toxicosis of wildlife in laboratory feeding studies. While low in free selenomethionine, microphytes isolated from Se-laden agricultural evaporation ponds were abundant in proteinaceous selenomethionine. This prompted a more extensive survey of Se speciation in foodchain organisms including microphytes, macroinvertebrates, fish, and bird embryos residing mainly in the agricultural drainage systems of the San Joaquin Valley, California. Total Se in biomass, water-soluble fractions, and protein-rich fractions were measured along with GC-MS analysis of proteinaceous selenomethionine. In all foodchain organisms, water-soluble Se constituted the major fraction of total biomass Se, while proteinaceous Se was a substantial, if not dominant, fraction of the water-soluble Se. In turn, proteinaceous selenomethionine comprised an important fraction of proteinaceous Se. In terms of total biomass Se, an average 1400-fold of Se biomagnification from water to microphytes was observed while subsequent transfer from microphytes to macroinvertebrates exhibited an average of only 1.9-fold. The latter transfer was more consistent and greater in extent for proteinaceous Se and proteinaceous selenomethionine, which

  16. Congenital diaphragmatic hernia and microtia in a newborn with mycophenolate mofetil (MMF) exposure: phenocopy for Fryns syndrome or broad spectrum of teratogenic effects?

    Science.gov (United States)

    Parisi, Melissa A; Zayed, Hatem; Slavotinek, Anne M; Rutledge, Joe C

    2009-06-01

    A newborn female infant born to a woman on immunosuppressive medications including mycophenolate mofetil (MMF) for a renal graft secondary to lupus nephritis presented with congenital diaphragmatic hernia (CDH) and additional findings of microtia, esophageal atresia with tracheoesophageal fistula, cleft palate, congenital heart defect, digital anomalies, and dysmorphic facial features. Pulmonary hypoplasia resulted in death at day 2 of life. She was presumed to have Fryns syndrome based on diagnostic criteria established for this recessive disorder with prominent features including CDH, facial anomalies, and nail hypoplasia. In retrospect, this infant's findings are more likely the result of teratogenic exposure to MMF, as more recent data have emerged linking aural atresia, digital anomalies, and dysmorphic features to this drug. To date, this is the only human report of CDH in an infant with prenatal exposure to MMF, although the manufacturer's package insert alludes to animal studies with a broad spectrum of malformations, including CDH. Thus, a teratogenic exposure can mimic a known Mendelian genetic syndrome, and caution is urged in presuming a genetic etiology for infants with potential teratogenic exposure to relatively new drugs with limited published animal data.

  17. Proteasome Accessory Factor C (pafC) Is a novel gene Involved in Mycobacterium Intrinsic Resistance to broad-spectrum antibiotics - Fluoroquinolones

    Science.gov (United States)

    Li, Qiming; Xie, Longxiang; Long, Quanxin; Mao, Jinxiao; Li, Hui; Zhou, Mingliang; Xie, Jianping

    2015-01-01

    Antibiotics resistance poses catastrophic threat to global public health. Novel insights into the underlying mechanisms of action will inspire better measures to control drug resistance. Fluoroquinolones are potent and widely prescribed broad-spectrum antibiotics. Bacterial protein degradation pathways represent novel druggable target for the development of new classes of antibiotics. Mycobacteria proteasome accessory factor C (pafC), a component of bacterial proteasome, is involved in fluoroquinolones resistance. PafC deletion mutants are hypersensitive to fluoroquinolones, including moxifloxacin, norfloxacin, ofloxacin, ciprofloxacin, but not to other antibiotics such as isoniazid, rifampicin, spectinomycin, chloramphenicol, capreomycin. This phenotype can be restored by complementation. The pafC mutant is hypersensitive to H2O2 exposure. The iron chelator (bipyridyl) and a hydroxyl radical scavenger (thiourea) can abolish the difference. The finding that pafC is a novel intrinsic selective resistance gene provided new evidence for the bacterial protein degradation pathway as druggable target for the development of new class of antibiotics. PMID:26139381

  18. Overexpression of MoSM1, encoding for an immunity-inducing protein from Magnaporthe oryzae, in rice confers broad-spectrum resistance against fungal and bacterial diseases

    Science.gov (United States)

    Hong, Yongbo; Yang, Yayun; Zhang, Huijuan; Huang, Lei; Li, Dayong; Song, Fengming

    2017-01-01

    Potential of MoSM1, encoding for a cerato-platanin protein from Magnaporthe oryzae, in improvement of rice disease resistance was examined. Transient expression of MoSM1 in rice leaves initiated hypersensitive response and upregulated expression of defense genes. When transiently expressed in tobacco leaves, MoSM1 targeted to plasma membrane. The MoSM1-overexpressing (MoSM1-OE) transgenic rice lines showed an improved resistance, as revealed by the reduced disease severity and decreased in planta pathogen growth, against 2 strains belonging to two different races of M. oryzae, causing blast disease, and against 2 strains of Xanthomonas oryzae pv. oryzae, causing bacterial leaf blight disease. However, no alteration in resistance to sheath blight disease was observed in MoSM1-OE lines. The MoSM1-OE plants contained elevated levels of salicylic acid (SA) and jasmonic acid (JA) and constitutively activated the expression of SA and JA signaling-related regulatory and defense genes. Furthermore, the MoSM1-OE plants had no effect on drought and salt stress tolerance and on grain yield. We conclude that MoSM1 confers a broad-spectrum resistance against different pathogens through modulating SA- and JA-mediated signaling pathways without any penalty on abiotic stress tolerance and grain yield, providing a promising potential for application of MoSM1 in improvement of disease resistance in crops. PMID:28106116

  19. RNA-dependent RNA polymerase (NIb) of the potyviruses is an avirulence factor for the broad-spectrum resistance gene Pvr4 in Capsicum annuum cv. CM334.

    Science.gov (United States)

    Kim, Saet-Byul; Lee, Hye-Young; Seo, Seungyeon; Lee, Joo Hyun; Choi, Doil

    2015-01-01

    Potyviruses are one of the most destructive viral pathogens of Solanaceae plants. In Capsicum annuum landrace CM334, a broad-spectrum gene, Pvr4 is known to be involved in resistance against multiple potyviruses, including Pepper mottle virus (PepMoV), Pepper severe mosaic virus (PepSMV), and Potato virus Y (PVY). However, a potyvirus avirulence factor against Pvr4 has not been identified. To identify the avirulence factor corresponding to Pvr4 in potyviruses, we performed Agrobacterium-mediated transient expressions of potyvirus protein coding regions in potyvirus-resistant (Pvr4) and -susceptible (pvr4) pepper plants. Hypersensitive response (HR) was observed only when a RNA-dependent RNA polymerase (NIb) of PepMoV, PepSMV, or PVY was expressed in Pvr4-bearing pepper leaves in a genotype-specific manner. In contrast, HR was not observed when the NIb of Tobacco etch virus (TEV), a virulent potyvirus, was expressed in Pvr4-bearing pepper leaves. Our results clearly demonstrate that NIbs of PepMoV, PepSMV, and PVY serve as avirulence factors for Pvr4 in pepper plants.

  20. Alfalfa benefits from Medicago truncatula: the RCT1 gene from M. truncatula confers broad-spectrum resistance to anthracnose in alfalfa.

    Science.gov (United States)

    Yang, Shengming; Gao, Muqiang; Xu, Chenwu; Gao, Jianchang; Deshpande, Shweta; Lin, Shaoping; Roe, Bruce A; Zhu, Hongyan

    2008-08-26

    Alfalfa is economically the most important forage legume worldwide. A recurrent challenge to alfalfa production is the significant yield loss caused by disease. Although knowledge of molecular mechanisms underlying host resistance should facilitate the genetic improvement of alfalfa, the acquisition of such knowledge is hampered by alfalfa's tetrasomic inheritance and outcrossing nature. However, alfalfa is congeneric with the reference legume Medicago truncatula, providing an opportunity to use M. truncatula as a surrogate to clone the counterparts of many agronomically important genes in alfalfa. In particular, the high degree of sequence identity and remarkably conserved genome structure and function between the two species enables M. truncatula genes to be used directly in alfalfa improvement. Here we report the map-based cloning of RCT1, a host resistance (R) gene in M. truncatula that confers resistance to multiple races of Colletotrichum trifolii, a hemibiotrophic fungal pathogen that causes anthracnose disease of alfalfa. RCT1 is a member of the Toll-interleukin-1 receptor/nucleotide-binding site/leucine-rich repeat (TIR-NBS-LRR) class of plant R genes and confers broad-spectrum anthracnose resistance when transferred into susceptible alfalfa plants. Thus, RCT1 provides a novel resource to develop anthracnose-resistant alfalfa cultivars and contributes to our understanding of host resistance against the fungal genus Colletotrichum. This work demonstrates the potential of using M. truncatula genes for genetic improvement of alfalfa.

  1. Varespladib (LY315920 Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation

    Directory of Open Access Journals (Sweden)

    Matthew Lewin

    2016-08-01

    Full Text Available Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2 activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2 inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite.

  2. Antimicrobial interactions (synergy) of teicoplanin with two broad-spectrum drugs (cefotaxime, ofloxacin) tested against gram-positive isolates from Germany and the United States.

    Science.gov (United States)

    Jones, R N; Marshall, S A; Grimm, H

    1997-10-01

    Teicoplanin, a glycopeptide, has been widely used in some nations alone and in empiric therapy combinations to address infections caused by Gram-positive cocci. However, glycopeptide resistance and the increasing incidence of oxacillin-resistant staphylococci have compromised contemporary chemotherapy. In this study, teicoplanin was tested in combinations with ampicillin, cefotaxime with and without desacetylcefotaxime, and ofloxacin against 151 Gram-positive cocci to assess the potential for enhanced action. The strains included recent isolates from the United States and Germany having well-characterized resistance mechanisms (oxacillin-resistant staphylococci, vancomycin-resistant enterococci), each tested by NCCLS methods, checkerboard synergy tests, and kill-curves. Teicoplanin alone was active (MIC90s, 0.25-2 micrograms/mL) against all species except vanA enterococci. Drug interactions of teicoplanin with beta-lactams revealed synergy and partial synergy versus oxacillin-resistant Staphylococcus spp. (67-100%) and vancomycin-resistant enterococci (70-100%), many at clinically achievable drug concentrations. However, confirming kill-curve experiments showed static action and no significant bactericidal effect. Combinations of ofloxacin with teicoplanin or cefotaxime plus desacetylcefotaxime showed a dominant additive and indifferent interaction. Teicoplanin continues to be a viable alternative to vancomycin, especially in combination therapy with selected broad-spectrum cephalosporins or fluoroquinolones. Many emerging pathogens that test resistant to individual drugs appear to be inhibited by tested combinations, extending their potential clinical utility.

  3. GhMPK7, a novel multiple stress-responsive cotton group C MAPK gene, has a role in broad spectrum disease resistance and plant development.

    Science.gov (United States)

    Shi, Jing; An, Hai-Long; Zhang, Liang; Gao, Zheng; Guo, Xing-Qi

    2010-09-01

    Mitogen-activated protein kinase (MAPK) cascades play a pivotal role in environmental responses and developmental processes in plants. Previous researches mainly focus on the MAPKs in groups A and B, and little is known on group C. In this study, we isolated and characterized GhMPK7, which is a novel gene from cotton belonging to the group C MAPK. RNA blot analysis indicated that GhMPK7 transcript was induced by pathogen infection and multiple defense-related signal molecules. Transgenic Nicotina benthamiana overexpressing GhMPK7 displayed significant resistance to fungus Colletotrichum nicotianae and virus PVY, and the transcript levels of SA pathway genes were more rapidly and strongly induced. Furthermore, the transgenic N. benthamiana showed reduced ROS-mediated injuries by upregulating expression of oxidative stress-related genes. Interestingly, the transgenic plants germinated earlier and grew faster in comparison to wild-type plants. beta-glucuronidase activity driven by the GhMPK7 promoter was detected in the apical meristem at the vegetative stage, and it was enhanced by treatments with signal molecules and phytohormones. These results suggest that GhMPK7 might play an important role in SA-regulated broad-spectrum resistance to pathogen infection, and that it is also involved in regulation of plant growth and development.

  4. A novel broad-spectrum cephalosporin ceftobiprole%新型广谱头孢菌素类抗菌药物头孢吡普

    Institute of Scientific and Technical Information of China (English)

    熊礼玲; 游莉; 刘家健; 李栋宏

    2011-01-01

    Antimicrobial resistance has become a significant problem over the past decade with marked increases in the incidence of MRSA, intermediate- and high level resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant enterococci. Ceftobiprole was the first of a new class of broad-spectrum cephalosporin antibiotics that had potent antibacterial activity towards methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Staphylococcus aureus (VRSA). This review detailed its mechanism of action, synthesis methods, antibacterial activities in vivo, pharmacokinetic profie and clinical trials.%随着耐甲氧西林金葡萄球菌、耐药金黄色葡萄球菌、耐青霉素肺炎链球菌和耐万古霉素肠球菌显著增加,细菌耐药性成为近年来一个重大难题.Ceftobiprole是第一个对耐甲氧西林金葡萄球菌(MRSA)和万古霉素耐药金黄色葡葡球菌(VRSA)有效的广谱头孢菌素类抗生素.现对其作用机制、合成路线、体外抗菌活性、药动学特性、临床试验等方面作一综述.

  5. Inheritance studies of apple scab resistance and identification of Rvi14, a new major gene that acts together with other broad-spectrum QTL.

    Science.gov (United States)

    Soufflet-Freslon, V; Gianfranceschi, L; Patocchi, A; Durel, C-E

    2008-08-01

    Scab, caused by the fungal pathogen Venturia inaequalis, is the most common disease of cultivated apple (Malus xdomestica). The fungal races 6 and 7 have now overcome the major resistance gene Vf, which is widely used in apple breeding programmes. New breeding strategies to achieve durable resistance are thus necessary. The aim of this study was to determine the genetic basis of quantitative resistance of the apple cultivar 'Dülmener Rosenapfel', known to be scab resistant under different environmental conditions. An F1 progeny derived from the cross between the susceptible cultivar 'Gala' and 'Dülmener Rosenapfel' was tested in a greenhouse with a multi-isolate inoculum of V. inaequalis. Rvi14, a new major gene that conditions a chlorotic-type reaction, was mapped on linkage group (LG) 6 in a genomic region not known to be involved in disease resistance. A further three quantitative trait loci (QTL) for resistance were identified. One co-localized with Rvi14 on LG6, whereas the remaining two were detected on LG11 and LG17, in genomic regions already reported to carry broad-spectrum QTL in other genetic backgrounds. Since a selective genotyping approach was used to detect QTL, an expectation-maximization (EM) computation was used to estimate the corrected QTL contributions to phenotypic variation and was validated by entire progeny genotyping.

  6. Protease-sensitive conformers in broad spectrum of distinct PrPSc structures in sporadic Creutzfeldt-Jakob disease are indicator of progression rate.

    Directory of Open Access Journals (Sweden)

    Chae Kim

    2011-09-01

    Full Text Available The origin, range, and structure of prions causing the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD, are largely unknown. To investigate the molecular mechanism responsible for the broad phenotypic variability of sCJD, we analyzed the conformational characteristics of protease-sensitive and protease-resistant fractions of the pathogenic prion protein (PrP(Sc using novel conformational methods derived from a conformation-dependent immunoassay (CDI. In 46 brains of patients homozygous for polymorphisms in the PRNP gene and exhibiting either Type 1 or Type 2 western blot pattern of the PrP(Sc, we identified an extensive array of PrP(Sc structures that differ in protease sensitivity, display of critical domains, and conformational stability. Surprisingly, in sCJD cases homozygous for methionine or valine at codon 129 of the PRNP gene, the concentration and stability of protease-sensitive conformers of PrP(Sc correlated with progression rate of the disease. These data indicate that sCJD brains exhibit a wide spectrum of PrP(Sc structural states, and accordingly argue for a broad spectrum of prion strains coding for different phenotypes. The link between disease duration, levels, and stability of protease-sensitive conformers of PrP(Sc suggests that these conformers play an important role in the pathogenesis of sCJD.

  7. Use of artificial intelligence in the design of small peptide antibiotics effective against a broad spectrum of highly antibiotic-resistant superbugs.

    Science.gov (United States)

    Cherkasov, Artem; Hilpert, Kai; Jenssen, Håvard; Fjell, Christopher D; Waldbrook, Matt; Mullaly, Sarah C; Volkmer, Rudolf; Hancock, Robert E W

    2009-01-16

    Increased multiple antibiotic resistance in the face of declining antibiotic discovery is one of society's most pressing health issues. Antimicrobial peptides represent a promising new class of antibiotics. Here we ask whether it is possible to make small broad spectrum peptides employing minimal assumptions, by capitalizing on accumulating chemical biology information. Using peptide array technology, two large random 9-amino-acid peptide libraries were iteratively created using the amino acid composition of the most active peptides. The resultant data was used together with Artificial Neural Networks, a powerful machine learning technique, to create quantitative in silico models of antibiotic activity. On the basis of random testing, these models proved remarkably effective in predicting the activity of 100,000 virtual peptides. The best peptides, representing the top quartile of predicted activities, were effective against a broad array of multidrug-resistant "Superbugs" with activities that were equal to or better than four highly used conventional antibiotics, more effective than the most advanced clinical candidate antimicrobial peptide, and protective against Staphylococcus aureus infections in animal models.

  8. Activity of broad-spectrum and reduced-risk insecticides on various life stages of cranberry fruitworm (Lepidoptera: Pyralidae) in highbush blueberry.

    Science.gov (United States)

    Wise, John C; Jenkins, Paul E; Poppen, Ryan Vander; Isaacs, Rufus

    2010-10-01

    Laboratory and semifield bioassays were conducted to determine the life-stage activity of insecticides for controlling cranberry fruitworm, Acrobasis vaccinii Riley (Lepidoptera: Pyralidae), a key lepidopteran pest of highbush blueberry, Vaccinium corymbosum L. The organophosphates azinphosmethyl and phosmet, the pyrethroid esfenvalerate, and the carbamate methomyl were lethal to all life stages. The neonicotinoids thiacloprid and acetamiprid demonstrated strong larvicidal and ovicidal activity but were somewhat weaker adulticides than the conventional broad-spectrum compounds. Bacillus thuringiensis, indoxacarb, and emamectin benzoate were shown to control A. vacinii primarily through their larvicidal activity. Spinosad was toxic to all life stages, including eggs laid on top of residues and those that were treated topically, but larvicidal activity was short lived. The growth regulators pyriproxyfen and novaluron had strong ovicidal activity when eggs were laid on top of residues but had limited larvicidal activity. Tebufenozide was not directly toxic to eggs, but demonstrated larvicidal activity, and ovilarvicidal activity when topically applied to eggs. Azinphosmethyl, phosmet, indoxacarb, thiacloprid, and acetamiprid were all toxic to the egg parasitoid Trichogramma minutum Riley. In contrast pyriproxyfen, emamectin benzoate, methomyl, novaluron, and spinosad did not negatively affect the survival of T. minutum within Acrobasis vacinii eggs. These results help inform the ongoing development of integrated strategies for insect management in blueberry.

  9. Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation

    Science.gov (United States)

    Lewin, Matthew; Samuel, Stephen; Merkel, Janie; Bickler, Philip

    2016-01-01

    Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2) activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2) inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases) could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite. PMID:27571102

  10. Nuclear Magnetic Resonance Solution Structures of Lacticin Q and Aureocin A53 Reveal a Structural Motif Conserved among Leaderless Bacteriocins with Broad-Spectrum Activity.

    Science.gov (United States)

    Acedo, Jeella Z; van Belkum, Marco J; Lohans, Christopher T; Towle, Kaitlyn M; Miskolzie, Mark; Vederas, John C

    2016-02-02

    Lacticin Q (LnqQ) and aureocin A53 (AucA) are leaderless bacteriocins from Lactococcus lactis QU5 and Staphylococcus aureus A53, respectively. These bacteriocins are characterized by the absence of an N-terminal leader sequence and are active against a broad range of Gram-positive bacteria. LnqQ and AucA consist of 53 and 51 amino acids, respectively, and have 47% identical sequences. In this study, their three-dimensional structures were elucidated using solution nuclear magnetic resonance and were shown to consist of four α-helices that assume a very similar compact, globular overall fold (root-mean-square deviation of 1.7 Å) with a highly cationic surface and a hydrophobic core. The structures of LnqQ and AucA resemble the shorter two-component leaderless bacteriocins, enterocins 7A and 7B, despite having low levels of sequence identity. Homology modeling revealed that the observed structural motif may be shared among leaderless bacteriocins with broad-spectrum activity against Gram-positive organisms. The elucidated structures of LnqQ and AucA also exhibit some resemblance to circular bacteriocins. Despite their similar overall fold, inhibition studies showed that LnqQ and AucA have different antimicrobial potency against the Gram-positive strains tested, suggesting that sequence disparities play a crucial role in their mechanisms of action.

  11. Transplastomic Nicotiana benthamiana plants expressing multiple defence genes encoding protease inhibitors and chitinase display broad-spectrum resistance against insects, pathogens and abiotic stresses.

    Science.gov (United States)

    Chen, Peng-Jen; Senthilkumar, Rajendran; Jane, Wann-Neng; He, Yong; Tian, Zhihong; Yeh, Kai-Wun

    2014-05-01

    Plastid engineering provides several advantages for the next generation of transgenic technology, including the convenient use of transgene stacking and the generation of high expression levels of foreign proteins. With the goal of generating transplastomic plants with multiresistance against both phytopathogens and insects, a construct containing a monocistronic patterned gene stack was transformed into Nicotiana benthamiana plastids harbouring sweet potato sporamin, taro cystatin and chitinase from Paecilomyces javanicus. Transplastomic lines were screened and characterized by Southern/Northern/Western blot analysis for the confirmation of transgene integration and respective expression level. Immunogold localization analyses confirmed the high level of accumulation proteins that were specifically expressed in leaf and root plastids. Subsequent functional bioassays confirmed that the gene stacks conferred a high level of resistance against both insects and phytopathogens. Specifically, larva of Spodoptera litura and Spodoptera exigua either died or exhibited growth retardation after ingesting transplastomic plant leaves. In addition, the inhibitory effects on both leaf spot diseases caused by Alternaria alternata and soft rot disease caused by Pectobacterium carotovorum subsp. carotovorum were markedly observed. Moreover, tolerance to abiotic stresses such as salt/osmotic stress was highly enhanced. The results confirmed that the simultaneous expression of sporamin, cystatin and chitinase conferred a broad spectrum of resistance. Conversely, the expression of single transgenes was not capable of conferring such resistance. To the best of our knowledge, this is the first study to demonstrate an efficacious stacked combination of plastid-expressed defence genes which resulted in an engineered tolerance to various abiotic and biotic stresses.

  12. Broad spectrum β-lactam resistance in faecal Escherichia coli isolated from severely malnourished and nourished children attending Mbagathi district hospital, Nairobi: A case-control study

    Directory of Open Access Journals (Sweden)

    Samuel Mwangi Njoroge

    2014-01-01

    Full Text Available Context: Severely malnourished children have increased risk of being put on antibiotics due to co-morbidities. Aim: The study′s objective was to characterize the Escherichia coli β-lactamase mediated resistance to the broad spectrum β-lactam antimicrobials among this population and compare them with nourished children as controls. Settings and Design: In this case-control, hospital-based setup, 109 E. coli isolates were obtained from each group, one isolate per subject. Materials and Methods: Stool or anal swabs were collected, enriched in buffered peptone water and cultured on MacConkey and eosin methylene blue agars. Biochemical test were used to identify E. coli. antibiograms to determine phenotypic resistance were determined using a panel of 14 drugs. Only the isolates showing synergy between ampicillin-calvulanic acid and one or more third generation cephalosporins were picked as extended spectrum β-lactamase (ESBL producers. Statistical Analysis: Differences in ESBL rates and susceptibility percentages between cases and controls were evaluated for significance using 2-tailed Fisher′s exact test. Results: Prevalence of ESBL phenotype was higher in severely malnourished children (39% as compared to the controls (7%. The plasmid-encoded AmpC′s (pAmpC-like phenotype was observed in 11% isolates. Conclusions: Isolation of ESBL-E. coli among severely malnourished children is high. Surveillance of ESBL producers, both in the community and hospital settings needs to be stepped up in Kenya.

  13. The effect of heating temperature and nitric acid treatments on the performance of Cu- and Zn-based broad spectrum respirator carbons.

    Science.gov (United States)

    Smith, J W H; Romero, J V; Dahn, T R; Dunphy, K; Sullivan, B; Mallay, M; Croll, L M; Reynolds, J H; Andress, C; Dahn, J R

    2011-12-01

    Impregnated activated carbons (IACs) that are used in broad spectrum gas mask applications have historically contained copper and/or zinc impregnants. The addition of an oxidizing agent, such as nitric acid (HNO(3)) can be useful in distributing the metallic impregnants uniformly on the activated carbon substrate. In this work, we study IACs prepared from copper nitrate (Cu(NO(3))(2)) and zinc nitrate (Zn(NO(3))(2)) precursors as a function of HNO(3) content present in the impregnating solution and as a function of heating temperature. The gas adsorption capacity of the IACs was determined by dynamic flow testing using sulfur dioxide (SO(2)), ammonia (NH(3)), hydrogen cyanide (HCN) and cyclohexane (C(6)H(12)) challenge gases under dry and humid conditions. The thermal decomposition and distribution of the impregnant on the activated carbon substrate is studied using X-ray diffraction (XRD), scanning electron microscopy (SEM) and thermal analysis techniques. Relationships between gas adsorption capacity, impregnant distribution and the species of surface impregnants are discussed.

  14. Discovery and development of kibdelomycin, a new class of broad-spectrum antibiotics targeting the clinically proven bacterial type II topoisomerase.

    Science.gov (United States)

    Singh, Sheo B

    2016-12-15

    Kibdelomycin is a complex novel antibiotic, discovered by applying a highly sophisticated chemical-genetic Staphylococcus aureus Fitness Test (SaFT) approach, that inhibits the clinically established bacterial targets, gyrase and topoisomerase IV. It exhibits broad-spectrum antibacterial activity against aerobic bacteria including MRSA and Acinetobacter baumannii. It is slowly bactericidal and has a low frequency of resistance. In an anaerobic environment, it exhibits narrow-spectrum activity and inhibits the growth of gut bacteria Clostridium difficile (MIC 0.125μg/mL) without affecting the growth of commensal Gram-negative organisms particularly, Bacteroides sp. It is highly efficacious in the hamster model of C. difficile infection providing 100% protection at >6mg/kg and 80% protection at 1.56mg/kg by oral dosing without systemic exposure. X-ray co-crystal structures of kibdelomycin bound to GyrB and ParE showed a unique dual arm 'U shaped' multisite binding never encountered with any other gyrase inhibitors. Kibdelomycin is poised for preclinical development for C. difficile treatment, and most importantly, the co-crystal structures of kibdelomycin provide unique insight for structure-guided structure modification, which could lead to better broader-spectrum systemic antibiotic potentially covering many ESKAPE pathogens. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Tallow amphopolycarboxyglycinate-stabilized silver nanoparticles: new frontiers in development of plant protection products with a broad spectrum of action against phytopathogens

    Science.gov (United States)

    Krutyakov, Yurii A.; Kudrinskiy, Alexey A.; Zherebin, Pavel M.; Yapryntsev, Alexey D.; Pobedinskaya, Marina A.; Elansky, Sergey N.; Denisov, Albert N.; Mikhaylov, Dmitry M.; Lisichkin, Georgii V.

    2016-07-01

    Sustainable agriculture calls for minimal use of agrochemicals in order to protect the environment. It has caused an increase in the rate of nanoparticles use, in particular silver nanoparticles (AgNPs) due to their safety for mammals, unique biological activity and a broad spectrum of action against fungal and bacterial pathogens. Until now the use of AgNPs dispersions in the agricultural sector has been essentially limited due to many factors decreased their stability (mixing with other pesticides, presence of electrolytes). We present a versatile synthesis of polyampholyte surfactant (tallow amphopolycarboxyglycinate) stabilized AgNPs. We took a close look at unique aggregation behavior (via dynamic light scattering and UV-vis spectroscopy) and biocidal activity of obtained silver colloids. AgNPs are characterized by exclusively high aggregative stability in the presence of coagulating agents NaNO3 and NaSO4 (up to 1 M), during drying/redispergation, and frost/defrost cycles. The dispersion of AgNPs shows high biocidal activity (EC50 is ten times lower than commercial species ones) with respect to Phytophthora infestans and phytopathogenic fungi. This points to the possibility of successful application of silver preparations within agriculture with the goal of partial reduction of the use of toxic and expensive synthetic antibiotics and pesticides.

  16. Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation.

    Science.gov (United States)

    Lewin, Matthew; Samuel, Stephen; Merkel, Janie; Bickler, Philip

    2016-08-25

    Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2) activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2) inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases) could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite.

  17. Characterization and Genetic Analysis of a Novel Rice Spotted-leaf Mutant HM47 with Broad-spectrum Resistance to Xanthomonas oryzae pv.oryzae(F)

    Institute of Scientific and Technical Information of China (English)

    Bao-Hua Feng; Yang Yang; Yong-Feng Shi; Hai-Chao Shen; Hui-Mei Wang; Qi-Na Huang; Xia Xu

    2013-01-01

    A stable inherited rice spotted-leaf mutant HM47 derived from an EMS-induced IR64 mutant bank was identified.The mutant expressed hypersensitive response (HR)-like symptoms throughout its whole life from the first leaf to the flag leaf,without pathogen invasion.Initiation of the lesions was induced by light under natural summer field conditions.Expression of pathogenesis-related genes including PAL,PO-C1,POX22.3 and PBZ1 was enhanced significantly in association with cell death and accumulation of H2O2 at and around the site of lesions in the mutant in contrast to that in the wild-type (WT).Disease reaction to Xanthomonas oryzae pv.oryzae from the Philippines and China showed that HM47 is a broad-spectrum disease-resistant mutant with enhanced resistance to multiple races of bacterial blight pathogens tested.An F2 progeny test showed that bacterial blight resistance to race HB-17 was cosegregated with the expression of lesions.Genetic analysis indicated that the spotted-leaf trait was controlled by a single recessive gene,tentatively named splHM47,flanked by two insertion/deletion markers in a region of approximately 74 kb on the long arm of chromosome 4.Ten open reading frames are predicted,and all of them are expressed proteins.Isolation and validation of the putative genes are currently underway.

  18. Evaluation of Carbohydrate-Derived Fulvic Acid (CHD-FA) as a Topical Broad-Spectrum Antimicrobial for Drug-Resistant Wound Infections

    Science.gov (United States)

    2015-10-01

    scattered accumulations of bacterial colonies between and on the cell layers as well as in hair follicles . Dermis denatured with minimal... hair follicles . The superficial dermis is multifocally disrupted with separation of collagen fibers. There is hypodermal and muscle layer edema and...MDR bacteria and antifungal-resistant fungi, the early use of CHD-FA is advantageous because it represents a novel target that will not select for

  19. Proteinaceous Pheromone Homologs Identified from the Cloacal Gland Transcriptome of a Male Axolotl, Ambystoma mexicanum.

    Directory of Open Access Journals (Sweden)

    Kevin W Hall

    Full Text Available Pheromones play an important role in modifying vertebrate behavior, especially during courtship and mating. Courtship behavior in urodele amphibians often includes female exposure to secretions from the cloacal gland, as well as other scent glands. The first vertebrate proteinaceous pheromone discovered, the decapeptide sodefrin, is a female attracting pheromone secreted by the cloacal gland of male Cynops pyrrhogaster. Other proteinaceous pheromones in salamanders have been shown to elicit responses from females towards conspecific males. The presence and levels of expression of proteinaceous pheromones have not been identified in the family Ambystomatidae, which includes several important research models. The objective of this research was therefore to identify putative proteinaceous pheromones from male axolotls, Ambystoma mexicanum, as well as their relative expression levels. The results indicate that axolotls possess two different forms of sodefrin precursor-like factor (alpha and beta, as well as a putative ortholog of plethodontid modulating factor. The beta form of sodefrin precursor-like factor was amongst the most highly expressed transcripts within the cloacal gland. The ortholog of plethodontid modulating factor was expressed at a level equivalent to the beta sodefrin precursor-like factor. The results are from a single male axolotl; therefore, we are unable to assess how representative our results may be. Nevertheless, the presence of these highly expressed proteinaceous pheromones suggests that male axolotls use multiple chemical cues to attract female conspecifics. Behavioral assays would indicate whether the putative protein pheromones elicit courtship activity from female axolotls.

  20. Proteinaceous Pheromone Homologs Identified from the Cloacal Gland Transcriptome of a Male Axolotl, Ambystoma mexicanum.

    Science.gov (United States)

    Hall, Kevin W; Eisthen, Heather L; Williams, Barry L

    2016-01-01

    Pheromones play an important role in modifying vertebrate behavior, especially during courtship and mating. Courtship behavior in urodele amphibians often includes female exposure to secretions from the cloacal gland, as well as other scent glands. The first vertebrate proteinaceous pheromone discovered, the decapeptide sodefrin, is a female attracting pheromone secreted by the cloacal gland of male Cynops pyrrhogaster. Other proteinaceous pheromones in salamanders have been shown to elicit responses from females towards conspecific males. The presence and levels of expression of proteinaceous pheromones have not been identified in the family Ambystomatidae, which includes several important research models. The objective of this research was therefore to identify putative proteinaceous pheromones from male axolotls, Ambystoma mexicanum, as well as their relative expression levels. The results indicate that axolotls possess two different forms of sodefrin precursor-like factor (alpha and beta), as well as a putative ortholog of plethodontid modulating factor. The beta form of sodefrin precursor-like factor was amongst the most highly expressed transcripts within the cloacal gland. The ortholog of plethodontid modulating factor was expressed at a level equivalent to the beta sodefrin precursor-like factor. The results are from a single male axolotl; therefore, we are unable to assess how representative our results may be. Nevertheless, the presence of these highly expressed proteinaceous pheromones suggests that male axolotls use multiple chemical cues to attract female conspecifics. Behavioral assays would indicate whether the putative protein pheromones elicit courtship activity from female axolotls.

  1. Icariside II, a Broad-Spectrum Anti-cancer Agent, Reverses Beta-Amyloid-Induced Cognitive Impairment through Reducing Inflammation and Apoptosis in Rats

    Science.gov (United States)

    Deng, Yuanyuan; Long, Long; Wang, Keke; Zhou, Jiayin; Zeng, Lingrong; He, Lianzi; Gong, Qihai

    2017-01-01

    Beta-amyloid (Aβ) deposition, associated neuronal apoptosis and neuroinflammation are considered as the important factors which lead to cognitive deficits in Alzheimer’s disease (AD). Icariside II (ICS II), an active flavonoid compound derived from Epimedium brevicornum Maxim, has been extensively used to treat erectile dysfunction, osteoporosis and dementia in traditional Chinese medicine. Recently, ICS II attracts great interest due to its broad-spectrum anti-cancer property. ICS II shows an anti-inflammatory potential both in cancer treatment and cerebral ischemia-reperfusion. It is not yet clear whether the anti-inflammatory effect of ICS II could delay progression of AD. Therefore, the current study aimed to investigate the effects of ICS II on the behavioral deficits, Aβ levels, neuroinflammatory responses and apoptosis in Aβ25-35-treated rats. We found that bilateral hippocampal injection of Aβ25-35 induced cognitive impairment, neuronal damage, along with increase of Aβ, inflammation and apoptosis in hippocampus of rats. However, treatment with ICS II 20 mg/kg could improve the cognitive deficits, ameliorate neuronal death, and reduce the levels of Aβ in the hippocampus. Furthermore, ICS II could suppress microglial and astrocytic activation, inhibit expression of IL-1β, TNF-α, COX-2, and iNOS mRNA and protein, and attenuate the Aβ induced Bax/Bcl-2 ratio elevation and caspase-3 activation. In conclusion, these results showed that ICS II could reverse Aβ-induced cognitive deficits, possibly via the inhibition of neuroinflammation and apoptosis, which suggested a potential protective effect of ICS II on AD. PMID:28210222

  2. A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models.

    Science.gov (United States)

    Zhao, Genshi; Li, Wei-Ying; Chen, Daohong; Henry, James R; Li, Hong-Yu; Chen, Zhaogen; Zia-Ebrahimi, Mohammad; Bloem, Laura; Zhai, Yan; Huss, Karen; Peng, Sheng-Bin; McCann, Denis J

    2011-11-01

    The fibroblast growth factor receptors (FGFR) are tyrosine kinases that are present in many types of endothelial and tumor cells and play an important role in tumor cell growth, survival, and migration as well as in maintaining tumor angiogenesis. Overexpression of FGFRs or aberrant regulation of their activities has been implicated in many forms of human malignancies. Therefore, targeting FGFRs represents an attractive strategy for development of cancer treatment options by simultaneously inhibiting tumor cell growth, survival, and migration as well as tumor angiogenesis. Here, we describe a potent, selective, small-molecule FGFR inhibitor, (R)-(E)-2-(4-(2-(5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol-3yl)vinyl)-1H-pyrazol-1-yl)ethanol, designated as LY2874455. This molecule is active against all 4 FGFRs, with a similar potency in biochemical assays. It exhibits a potent activity against FGF/FGFR-mediated signaling in several cancer cell lines and shows an excellent broad spectrum of antitumor activity in several tumor xenograft models representing the major FGF/FGFR relevant tumor histologies including lung, gastric, and bladder cancers and multiple myeloma, and with a well-defined pharmacokinetic/pharmacodynamic relationship. LY2874455 also exhibits a 6- to 9-fold in vitro and in vivo selectivity on inhibition of FGF- over VEGF-mediated target signaling in mice. Furthermore, LY2874455 did not show VEGF receptor 2-mediated toxicities such as hypertension at efficacious doses. Currently, this molecule is being evaluated for its potential use in the clinic.

  3. Linear biocompatible glyco-polyamidoamines as dual action mode virus infection inhibitors with potential as broad-spectrum microbicides for sexually transmitted diseases

    Science.gov (United States)

    Mauro, Nicolò; Ferruti, Paolo; Ranucci, Elisabetta; Manfredi, Amedea; Berzi, Angela; Clerici, Mario; Cagno, Valeria; Lembo, David; Palmioli, Alessandro; Sattin, Sara

    2016-09-01

    The initial steps of viral infections are mediated by interactions between viral proteins and cellular receptors. Blocking the latter with high-affinity ligands may inhibit infection. DC-SIGN, a C-type lectin receptor expressed by immature dendritic cells and macrophages, mediates human immunodeficiency virus (HIV) infection by recognizing mannose clusters on the HIV-1 gp120 envelope glycoprotein. Mannosylated glycodendrimers act as HIV entry inhibitors thanks to their ability to block this receptor. Previously, an amphoteric, but prevailingly cationic polyamidoamine named AGMA1 proved effective as infection inhibitor for several heparan sulfate proteoglycan-dependent viruses, such as human papilloma virus HPV-16 and herpes simplex virus HSV-2. An amphoteric, but prevailingly anionic PAA named ISA23 proved inactive. It was speculated that the substitution of mannosylated units for a limited percentage of AGMA1 repeating units, while imparting anti-HIV activity, would preserve the fundamentals of its HPV-16 and HSV-2 infection inhibitory activity. In this work, four biocompatible linear PAAs carrying different amounts of mannosyl-triazolyl pendants, Man-ISA7, Man-ISA14, Man-AGMA6.5 and Man-AGMA14.5, were prepared by reaction of 2-(azidoethyl)-α-D-mannopyranoside and differently propargyl-substituted AGMA1 and ISA23. All mannosylated PAAs inhibited HIV infection. Both Man-AGMA6.5 and Man-AGMA14.5 maintained the HPV-16 and HSV-2 activity of the parent polymer, proving broad-spectrum, dual action mode virus infection inhibitors.

  4. A broad spectrum, one-step reverse-transcription PCR amplification of the neuraminidase gene from multiple subtypes of influenza A virus

    Directory of Open Access Journals (Sweden)

    Chen Wenbin

    2008-07-01

    Full Text Available Abstract Background The emergence of high pathogenicity strains of Influenza A virus in a variety of human and animal hosts, with wide geographic distribution, has highlighted the importance of rapid identification and subtyping of the virus for outbreak management and treatment. Type A virus can be classified into subtypes according to the viral envelope glycoproteins, hemagglutinin and neuraminidase. Here we review the existing specificity and amplification of published primers to subtype neuraminidase genes and describe a new broad spectrum primer pair that can detect all 9 neuraminidase subtypes. Results Bioinformatic analysis of 3,337 full-length influenza A neuraminidase segments in the NCBI database revealed semi-conserved regions not previously targeted by primers. Two degenerate primers with M13 tags, NA8F-M13 and NA10R-M13 were designed from these regions and used to generate a 253 bp cDNA product. One-step RT-PCR testing was successful in 31/32 (97% cases using a touchdown protocol with RNA from over 32 different cultured influenza A virus strains representing the 9 neuraminidase subtypes. Frozen blinded clinical nasopharyngeal aspirates were also assayed and were mostly of subtype N2. The region amplified was direct sequenced and then used in database searches to confirm the identity of the template RNA. The RT-PCR fragment generated includes one of the mutation sites related to oseltamivir resistance, H274Y. Conclusion Our one-step RT-PCR assay followed by sequencing is a rapid, accurate, and specific method for detection and subtyping of different neuraminidase subtypes from a range of host species and from different geographical locations.

  5. Co-administration of the broad-spectrum antiviral, brincidofovir (CMX001), with smallpox vaccine does not compromise vaccine protection in mice challenged with ectromelia virus.

    Science.gov (United States)

    Parker, Scott; Crump, Ryan; Foster, Scott; Hartzler, Hollyce; Hembrador, Ed; Lanier, E Randall; Painter, George; Schriewer, Jill; Trost, Lawrence C; Buller, R Mark

    2014-11-01

    Natural orthopoxvirus outbreaks such as vaccinia, cowpox, cattlepox and buffalopox continue to cause morbidity in the human population. Monkeypox virus remains a significant agent of morbidity and mortality in Africa. Furthermore, monkeypox virus's broad host-range and expanding environs make it of particular concern as an emerging human pathogen. Monkeypox virus and variola virus (the etiological agent of smallpox) are both potential agents of bioterrorism. The first line response to orthopoxvirus disease is through vaccination with first-generation and second-generation vaccines, such as Dryvax and ACAM2000. Although these vaccines provide excellent protection, their widespread use is impeded by the high level of adverse events associated with vaccination using live, attenuated virus. It is possible that vaccines could be used in combination with antiviral drugs to reduce the incidence and severity of vaccine-associated adverse events, or as a preventive in individuals with uncertain exposure status or contraindication to vaccination. We have used the intranasal mousepox (ectromelia) model to evaluate the efficacy of vaccination with Dryvax or ACAM2000 in conjunction with treatment using the broad spectrum antiviral, brincidofovir (BCV, CMX001). We found that co-treatment with BCV reduced the severity of vaccination-associated lesion development. Although the immune response to vaccination was quantifiably attenuated, vaccination combined with BCV treatment did not alter the development of full protective immunity, even when administered two days following ectromelia challenge. Studies with a non-replicating vaccine, ACAM3000 (MVA), confirmed that BCV's mechanism of attenuating the immune response following vaccination with live virus was, as expected, by limiting viral replication and not through inhibition of the immune system. These studies suggest that, in the setting of post-exposure prophylaxis, co-administration of BCV with vaccination should be considered

  6. Design, synthesis and crystallographic analysis of nitrile-based broad-spectrum peptidomimetic inhibitors for coronavirus 3C-like proteases.

    Science.gov (United States)

    Chuck, Chi-Pang; Chen, Chao; Ke, Zhihai; Wan, David Chi-Cheong; Chow, Hak-Fun; Wong, Kam-Bo

    2013-01-01

    Coronaviral infection is associated with up to 5% of respiratory tract diseases. The 3C-like protease (3CL(pro)) of coronaviruses is required for proteolytic processing of polyproteins and viral replication, and is a promising target for the development of drugs against coronaviral infection. We designed and synthesized four nitrile-based peptidomimetic inhibitors with different N-terminal protective groups and different peptide length, and examined their inhibitory effect on the in-vitro enzymatic activity of 3CL(pro) of severe-acute-respiratory-syndrome-coronavirus. The IC(50) values of the inhibitors were in the range of 4.6-49 μM, demonstrating that the nitrile warhead can effectively inactivate the 3CL(pro) autocleavage process. The best inhibitor, Cbz-AVLQ-CN with an N-terminal carbobenzyloxy group, was ~10x more potent than the other inhibitors tested. Crystal structures of the enzyme-inhibitor complexes showed that the nitrile warhead inhibits 3CL(pro) by forming a covalent bond with the catalytic Cys145 residue, while the AVLQ peptide forms a number of favourable interactions with the S1-S4 substrate-binding pockets. We have further showed that the peptidomimetic inhibitor, Cbz-AVLQ-CN, has broad-spectrum inhibition against 3CL(pro) from human coronavirus strains 229E, NL63, OC43, HKU1, and infectious bronchitis virus, with IC(50) values ranging from 1.3 to 3.7 μM, but no detectable inhibition against caspase-3. In summary, we have shown that the nitrile-based peptidomimetic inhibitors are effective against 3CL(pro), and they inhibit 3CL(pro) from a broad range of coronaviruses. Our results provide further insights into the future design of drugs that could serve as a first line defence against coronaviral infection. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  7. Structure activity relationship of pyridoxazinone substituted RHS analogs of oxabicyclooctane-linked 1,5-naphthyridinyl novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-6).

    Science.gov (United States)

    Singh, Sheo B; Kaelin, David E; Wu, Jin; Miesel, Lynn; Tan, Christopher M; Meinke, Peter T; Olsen, David B; Lagrutta, Armando; Wei, Changqing; Liao, Yonggang; Peng, Xuanjia; Wang, Xiu; Fukuda, Hideyuki; Kishii, Ryuta; Takei, Masaya; Yajima, Masanobu; Shibue, Taku; Shibata, Takeshi; Ohata, Kohei; Nishimura, Akinori; Fukuda, Yasumichi

    2015-09-01

    Oxabicyclooctane linked 1,5-naphthyridinyl-pyridoxazinones are novel broad-spectrum bacterial topoisomerase inhibitors (NBTIs) targeting bacterial DNA gyrase and topoisomerase IV at a site different than quinolones. Due to lack of cross-resistance to known antibiotics they present excellent opportunity to combat drug-resistant bacteria. A structure activity relationship of the pyridoxazinone moiety is described in this Letter. Chemical synthesis and activities of NBTIs with substitutions at C-3, C-4 and C-7 of the pyridoxazinone moiety with halogens, alkyl groups and methoxy group has been described. In addition, substitutions of the linker NH proton and its transformation into amide analogs of AM-8085 and AM-8191 have been reported. Fluoro, chloro, and methyl groups at C-3 of the pyridoxazinone moiety retained the potency and spectrum. In addition, a C-3 fluoro analog showed 4-fold better oral efficacy (ED50 3.9 mg/kg) as compared to the parent AM-8085 in a murine bacteremia model of infection of Staphylococcus aureus. Even modest polarity (e.g., methoxy) is not tolerated at C-3 of the pyridoxazinone unit. The basicity and NH group of the linker is important for the activity when CH2 is at the linker position-8. However, amides (with linker position-8 ketone) with a position-7 NH or N-methyl group retained potency and spectrum suggesting that neither basicity nor hydrogen-donor properties of the linker amide NH is essential for the activity. This would suggest likely an altered binding mode of the linker position-7,8 amide containing compounds. The amides showed highly improved hERG (functional IC50 >30 μM) profile.

  8. Characterization of Disopyramide derivative ADD424042 as a non-cardiotoxic neuronal sodium channel blocker with broad-spectrum anticonvulsant activity in rodent seizure models.

    Science.gov (United States)

    Król, Marek; Ufnal, Marcin; Szulczyk, Bartłomiej; Podsadni, Piotr; Drapała, Adrian; Turło, Jadwiga; Dawidowski, Maciej

    2016-01-01

    It was reported that antiarrhythmic drugs (AADs) can be useful in controlling refractory seizures in humans or in enhancing the action of antiepileptic drugs (AEDs) in animal models. Disopyramide phosphate (DISO) is an AAD that blocks sodium channels in cardiac myocytes. We evaluated a DISO derivative, 2-(2-chlorophenyl)-2-(pyridin-2-yl)acetamide (ADD424042) for its anticonvulsant activity in a battery of rodent models of epileptic seizures. The compound displayed a broad spectrum of activity in the 'classical' models as well as in the models of pharmacoresistant seizures. Furthermore, ADD424042 showed good therapeutic indices between the anticonvulsant activity and the motor impairment. On the contrary, no anticonvulsant effects but severe lethality were observed in the primary anticonvulsant testing of the parent DISO. By performing the whole-cell voltage-clamp experiments in dispersed cortical neurons we demonstrated that ADD424042 decreased the maximal amplitude of voltage-gated sodium channels with an IC50 value in nM range. Moreover, the compound enhanced use-dependent block and decreased excitability in pyramidal neurons in the current-clamp experiments in cortical slices. Importantly, we found that ADD424042 possessed either no, or very small cardiotoxic effect. In contrast to DISO, ADD424042 did not produce any apparent changes in electrocardiogram (ECG) and arterial blood pressure recordings. ADD424042 had no effect on QT and corrected QT intervals, at a dose which was 15 times higher than ED50 for the anticonvulsant effect in the MES model. Taken together, these data suggest that ADD424042 has the potential to become a lead structure for novel broadly acting AEDs with wide margin of cardiac safety.

  9. Natural herbicide resistance (HR) to broad-spectrum herbicide, glyphosate among traditional and inbred-cultivated rice (Oryza sativa L.) varieties in Sri Lanka.

    Science.gov (United States)

    Weerakoon, S R; Somaratne, S; Wijeratne, R G D; Ekanyaka, E M S I

    2013-08-15

    Weeds along with insect pests and plant diseases are sources of biotic stress in crop systems. Weeds are responsible for serious problems in rice worldwide affecting growth and causing a considerable reduction in quality and quantity in yield. High concentrations of pre-emergent-broad-spectrum systemic herbicide, Glyphosate is prevalently applied to control rice weeds which intern causes severe damages to cultivated rice varieties, susceptible to Glyphosate. However, there may be rice varieties with natural Herbicide Resistance (HR) which are so far, has not been evaluated. In this study Six traditional and eighteen developed-cultivated rice varieties (Bg, Bw, At and Ld series developed by Rice Research Development Institute, Sri Lanka) were used to screen their natural HR. RCBD with five replicates and three blocks in each treatment-combination was used as the experimental design. As observations, time taken-to seed germination, time taken to flowering; plant height and number of leaves at 12-weeks after sawing, leaf-length, breadth, panicle-length, number of seeds/panicle of resistant plants and controls were recorded. Plants with > or = 40% resistance were considered as resistant to Glyphosate. Ten inbred-cultivated rice varieties (Bg250, Bg94-1, Bg304, Bg359, Bg406, Bg379-2, Bg366, Bg300, Bw364, At362) and three traditional rice varieties ("Kalu Heenati", "Sudu Heenati", "Pachchaperumal") were naturally resistant to 0.25 g L(-1) Glyphosate concentration and when increased the concentration (0.5 g L(-1)) resistance was reduced. This study showed the usefulness of modern statistical method, classification and regression tree analysis (CART) in exploring and visualizing the patterns reflected by a large number of rice varieties (larger experimental database) on herbicide resistance in future.

  10. In vitro and clinical evaluation of SIG1273: a cosmetic functional ingredient with a broad spectrum of anti-aging and antioxidant activities.

    Science.gov (United States)

    Fernández, José R; Rouzard, Karl; Voronkov, Michael; Huber, Kristen L; Webb, Corey; Stock, Jeffry B; Stock, Maxwell; Gordon, Joel S; Pérez, Eduardo

    2016-06-01

    Isoprenylcysteine (IPC) small molecules were identified as a new class of anti-inflammatory compounds over 20 years ago. Since then, they have been developed as novel cosmetic functional ingredients (CFI) and topical drug candidates. SIG1273 is a second generation CFI that has previously been shown to provide a broad spectrum of benefits for the skin through its anti-inflammatory and antimicrobial properties. To determine whether SIG1273 possesses anti-aging properties in vitro and evaluate the tolerability and activity of SIG1273 when applied topically to human subjects. To model photoaging in vitro, human dermal fibroblasts (HDFs) were exposed in culture to UVA to induce collagenase (MMP-1) production. An in vitro wound-healing model was based on the activation of HDF migration into cell-free tissue culture surface. Hydrogen peroxide-induced oxidative stress was performed using HDFs to measure intracellular ROS activity. Radical scavenging capacity was determined using a colorimetric antioxidant assay kit (ABTS method). Lastly, a 4-week, 29-subject study was performed in which SIG1273 was applied topically as a cream to assess its tolerance and activity in reducing the appearance of aging. In vitro studies demonstrate SIG1273 inhibits UVA-induced MMP-1 production, hydrogen peroxide-induced oxidative stress and promotes wound healing. Moreover, SIG1273 was shown to be a radical scavenging antioxidant. Clinical assessment of SIG1273 cream (0.25%) showed it was well tolerated with significant improvement in the appearance of fine lines, coarse wrinkles, radiance/luminosity, pore size, texture/smoothness, hydration and increased firmness. SIG1273 represents a novel CFI with antioxidant, anti-aging, and anti-inflammatory properties that when applied topically is well tolerated and provides benefits to individuals with aging skin. © 2016 Wiley Periodicals, Inc.

  11. WRR4, a broad-spectrum TIR-NB-LRR gene from Arabidopsis thaliana that confers white rust resistance in transgenic oilseed Brassica crops.

    Science.gov (United States)

    Borhan, Mohammad Hossein; Holub, Eric B; Kindrachuk, Colin; Omidi, Mansour; Bozorgmanesh-Frad, Ghazaleh; Rimmer, S Roger

    2010-03-01

    White blister rust caused by Albugo candida (Pers.) Kuntze is a common and often devastating disease of oilseed and vegetable brassica crops worldwide. Physiological races of the parasite have been described, including races 2, 7 and 9 from Brassica juncea, B. rapa and B. oleracea, respectively, and race 4 from Capsella bursa-pastoris (the type host). A gene named WRR4 has been characterized recently from polygenic resistance in the wild brassica relative Arabidopsis thaliana (accession Columbia) that confers broad-spectrum white rust resistance (WRR) to all four of the above Al. candida races. This gene encodes a TIR-NB-LRR (Toll-like/interleukin-1 receptor-nucleotide binding-leucine-rich repeat) protein which, as with other known functional members in this subclass of intracellular receptor-like proteins, requires the expression of the lipase-like defence regulator, enhanced disease susceptibility 1 (EDS1). Thus, we used RNA interference-mediated suppression of EDS1 in a white rust-resistant breeding line of B. napus (transformed with a construct designed from the A. thaliana EDS1 gene) to determine whether defence signalling via EDS1 is functionally intact in this oilseed brassica. The eds1-suppressed lines were fully susceptible following inoculation with either race 2 or 7 isolates of Al. candida. We then transformed white rust-susceptible cultivars of B. juncea (susceptible to race 2) and B. napus (susceptible to race 7) with the WRR4 gene from A. thaliana. The WRR4-transformed lines were resistant to the corresponding Al. candida race for each host species. The combined data indicate that WRR4 could potentially provide a novel source of white rust resistance in oilseed and vegetable brassica crops.

  12. Induction of a peptide with activity against a broad spectrum of pathogens in the Aedes aegypti salivary gland, following Infection with Dengue Virus.

    Directory of Open Access Journals (Sweden)

    Natthanej Luplertlop

    2011-01-01

    Full Text Available The ultimate stage of the transmission of Dengue Virus (DENV to man is strongly dependent on crosstalk between the virus and the immune system of its vector Aedes aegypti (Ae. aegypti. Infection of the mosquito's salivary glands by DENV is the final step prior to viral transmission. Therefore, in the present study, we have determined the modulatory effects of DENV infection on the immune response in this organ by carrying out a functional genomic analysis of uninfected salivary glands and salivary glands of female Ae. aegypti mosquitoes infected with DENV. We have shown that DENV infection of salivary glands strongly up-regulates the expression of genes that encode proteins involved in the vector's innate immune response, including the immune deficiency (IMD and Toll signalling pathways, and that it induces the expression of the gene encoding a putative anti-bacterial, cecropin-like, peptide (AAEL000598. Both the chemically synthesized non-cleaved, signal peptide-containing gene product of AAEL000598, and the cleaved, mature form, were found to exert, in addition to antibacterial activity, anti-DENV and anti-Chikungunya viral activity. However, in contrast to the mature form, the immature cecropin peptide was far more effective against Chikungunya virus (CHIKV and, furthermore, had strong anti-parasite activity as shown by its ability to kill Leishmania spp. Results from circular dichroism analysis showed that the immature form more readily adopts a helical conformation which would help it to cause membrane permeabilization, thus permitting its transfer across hydrophobic cell surfaces, which may explain the difference in the anti-pathogenic activity between the two forms. The present study underscores not only the importance of DENV-induced cecropin in the innate immune response of Ae. aegypti, but also emphasizes the broad-spectrum anti-pathogenic activity of the immature, signal peptide-containing form of this peptide.

  13. Upregulated expression of La ribonucleoprotein domain family member 6 and collagen type I gene following water-filtered broad-spectrum near-infrared irradiation in a 3-dimensional human epidermal tissue culture model as revealed by microarray analysis.

    Science.gov (United States)

    Tanaka, Yohei; Nakayama, Jun

    2017-02-27

    Water-filtered broad-spectrum near-infrared irradiation can induce various biological effects, as our previous clinical, histological, and biochemical investigations have shown. However, few studies that examined the changes thus induced in gene expression. The aim was to investigate the changes in gene expression in a 3-dimensional reconstructed epidermal tissue culture exposed to water-filtered broad-spectrum near-infrared irradiation. DNA microarray and quantitative real-time polymerase chain reaction (PCR) analysis was used to assess gene expression levels in a 3-dimensional reconstructed epidermal model composed of normal human epidermal cells exposed to water-filtered broad-spectrum near-infrared irradiation. The water filter allowed 1000-1800 nm wavelengths and excluded 1400-1500 nm wavelengths, and cells were exposed to 5 or 10 rounds of near-infrared irradiation at 10 J/cm(2) . A DNA microarray with over 50 000 different probes showed 18 genes that were upregulated or downregulated by at least twofold after irradiation. Quantitative real-time PCR revealed that, relative to control cells, the gene encoding La ribonucleoprotein domain family member 6 (LARP6), which regulates collagen expression, was significantly and dose-dependently upregulated (P < 0.05) by water-filtered broad-spectrum near-infrared exposure. Gene encoding transcripts of collagen type I were significantly upregulated compared with controls (P < 0.05). This study demonstrates the ability of water-filtered broad-spectrum near-infrared irradiation to stimulate the production of type I collagen. © 2017 The Australasian College of Dermatologists.

  14. Releasing dye encapsulated in proteinaceous microspheres on conductive fabrics by electric current.

    Science.gov (United States)

    Shimanovich, Ulyana; Perelshtein, Ilana; Cavaco-Paulo, Artur; Gedanken, Aharon

    2012-06-27

    The current paper reports on the relase properties of conductive fabrics coated with proteinaceous microspheres containing a dye. The release of the dye was achieved by passing an electric current through the fabric. The conductivity of the polyester fibers resulted from nanosilver (Ag NPs) coated on the surface of these fibers. Both types of coatings (nanosilver coating and the coating of the proteinaceous microspheres) were performed using high-intensity ultrasonic waves. Two different types of dyes, hydrophilic RBBR (Remazol Brilliant Blue R) and hydrophobic ORO (Oil Red O), were encapsulated inside the microspheres (attached to the surface of polyester) and then released by applying an electric current. The Proteinaceous Microsphere (PM)-coated conductive fabrics could be used in medicine for drug release. The encapsulated dye can be replaced with a drug that could be released from the surface of fabrics by applying a low voltage.

  15. Antifungal nanoparticles and surfaces.

    Science.gov (United States)

    Paulo, Cristiana S O; Vidal, Maria; Ferreira, Lino S

    2010-10-11

    Nosocomial fungal infections, an increasing healthcare concern worldwide, are often associated with medical devices. We have developed antifungal nanoparticle conjugates that can act in suspension or attach to a surface, efficiently killing fungi. For that purpose, we immobilized covalently amphotericin B (AmB), a potent antifungal agent approved by the FDA, widely used in clinical practice and effective against a large spectrum of fungi, into silica nanoparticles. These antifungal nanoparticle conjugates are fungicidal against several strains of Candida sp., mainly by contact. In addition, they can be reused up to 5 cycles without losing their activity. Our results show that the antifungal nanoparticle conjugates are more fungistatic and fungicidal than 10 nm colloidal silver. The antifungal activity of the antifungal nanoparticle conjugates is maintained when they are immobilized on a surface using a chemical adhesive formed by polydopamine. The antifungal nanocoatings have no hemolytic or cytotoxic effect against red blood cells and blood mononuclear cells, respectively. Surfaces coated with these antifungal nanoparticle conjugates can be very useful to render medical devices with antifungal properties.

  16. Broad-spectrum efficacy across cognitive domains by alpha7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways.

    Science.gov (United States)

    Bitner, Robert S; Bunnelle, William H; Anderson, David J; Briggs, Clark A; Buccafusco, Jerry; Curzon, Peter; Decker, Michael W; Frost, Jennifer M; Gronlien, Jens Halvard; Gubbins, Earl; Li, Jinhe; Malysz, John; Markosyan, Stella; Marsh, Kennan; Meyer, Michael D; Nikkel, Arthur L; Radek, Richard J; Robb, Holly M; Timmermann, Daniel; Sullivan, James P; Gopalakrishnan, Murali

    2007-09-26

    The alpha7 nicotinic acetylcholine receptor (nAChR) plays an important role in cognitive processes and may represent a drug target for treating cognitive deficits in neurodegenerative and psychiatric disorders. In the present study, we used a novel alpha7 nAChR-selective agonist, 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) to interrogate cognitive efficacy, as well as examine potential cellular mechanisms of cognition. Exhibiting high affinity to native rat (Ki = 10.8 nM) and human (Ki = 16.7 nM) alpha7 nAChRs, A-582941 enhanced cognitive performance in behavioral assays including the monkey delayed matching-to-sample, rat social recognition, and mouse inhibitory avoidance models that capture domains of working memory, short-term recognition memory, and long-term memory consolidation, respectively. In addition, A-582941 normalized sensory gating deficits induced by the alpha7 nAChR antagonist methyllycaconitine in rats, and in DBA/2 mice that exhibit a natural sensory gating deficit. Examination of signaling pathways known to be involved in cognitive function revealed that alpha7 nAChR agonism increased extracellular-signal regulated kinase 1/2 (ERK1/2) phosphorylation in PC12 cells. Furthermore, increases in ERK1/2 and cAMP response element-binding protein (CREB) phosphorylation were observed in mouse cingulate cortex and/or hippocampus after acute A-582941 administration producing plasma concentrations in the range of alpha7 binding affinities and behavioral efficacious doses. The MEK inhibitor SL327 completely blocked alpha7 agonist-evoked ERK1/2 phosphorylation. Our results demonstrate that alpha7 nAChR agonism can lead to broad-spectrum efficacy in animal models at doses that enhance ERK1/2 and CREB phosphorylation/activation and may represent a mechanism that offers potential to improve cognitive deficits associated with neurodegenerative and psychiatric diseases, such as Alzheimer's disease and schizophrenia.

  17. Detection and characterization of broad-spectrum antipathogen activity of novel rhizobacterial isolates and suppression of Fusarium crown and root rot disease of tomato.

    Science.gov (United States)

    Zhang, L; Khabbaz, S E; Wang, A; Li, H; Abbasi, P A

    2015-03-01

    To detect and characterize broad-spectrum antipathogen activity of indigenous bacterial isolates obtained from potato soil and soya bean leaves for their potential to be developed as biofungicides to control soilborne diseases such as Fusarium crown and root rot of tomato (FCRR) caused by Fusarium oxysporum f. sp. radicis-lycopersici (Forl). Thirteen bacterial isolates (Bacillus amyloliquefaciens (four isolates), Paenibacillus polymyxa (three isolates), Pseudomonas chlororaphis (two isolates), Pseudomonas fluorescens (two isolates), Bacillus subtilis (one isolate) and Pseudomonas sp. (one isolate)) or their volatiles showed antagonistic activity against most of the 10 plant pathogens in plate assays. Cell-free culture filtrates (CF) of five isolates or 1-butanol extracts of CFs also inhibited the growth of most pathogen mycelia in plate assays. PCR analysis confirmed the presence of most antibiotic biosynthetic genes such as phlD, phzFA, prnD and pltC in most Pseudomonas isolates and bmyB, bacA, ituD, srfAA and fenD in most Bacillus isolates. These bacterial isolates varied in the production of hydrogen cyanide (HCN), siderophores, β-1,3-glucanases, chitinases, proteases, indole-3-acetic acid, salicylic acid, and for nitrogen fixation and phosphate solubilization. Gas chromatography-mass spectrometry analysis identified 10 volatile compounds from 10 isolates and 18 compounds from 1-butanol extracts of CFs of five isolates. Application of irradiated peat formulation of six isolates to tomato roots prior to transplanting in a Forl-infested potting mix and field soil provided protection of tomato plants from FCRR disease and enhanced plant growth under greenhouse conditions. Five of the 13 indigenous bacterial isolates were antagonistic to eight plant pathogens, both in vitro and in vivo. Antagonistic and plant-growth promotion activities of these isolates might be related to the production of several types of antibiotics, lytic enzymes, phytohormones, secondary

  18. Effects of a broad-spectrum caspase inhibitor, Z-VAD(OMe)-FMK, on viral hemorrhagic septicemia virus (VHSV) infection-mediated apoptosis and viral replication.

    Science.gov (United States)

    Kim, Min Sun; Lee, Ji Ae; Kim, Ki Hong

    2016-04-01

    In the development of inactivated or attenuated viral vaccines for cultured fish, viral titers harvested from the cultured cells would be the most important factor for the determination of vaccine's cost effectiveness. In this study, we hypothesized that the lengthening of cell survival time by the inhibition of apoptosis can lead to an increase of the final titer of viral hemorrhagic septicemia virus (VHSV). To test the hypothesis, we investigated the effects of a broad-spectrum caspase inhibitor, Z-VAD(OMe)-FMK, on VHSV infection-mediated apoptosis in Epithelioma papulosum cyprini (EPC) cells and on the VHSV titers. VHSV infection induced the DNA laddering in EPC cells, and the progression of DNA fragmentation was in proportion to the CPE extension. The progression of DNA fragmentation in EPC cells infected with VHSV was clearly inhibited by exposure to Z-VAD(OMe)-FMK, and the inhibition was intensified according to the increase of the inhibitor concentration. These results confirmed the previous reports that the death of host cells by VHSV infection is through apoptosis. Cells infected with a recombinant VHSV, rVHSV-ΔNV-eGFP, that was generated from our previous study by replacement of the NV gene ORF with the enhanced green fluorescent protein (eGFP) gene ORF, showed earlier and more distinct DNA fragmentations compared to the cells infected with wild-type VHSV, suggesting the inhibitory role of the NV protein in VHSV-mediated apoptosis that was previously reported. The final viral titers in the supernatant isolated from Z-VAD(OMe)-FMK treated cells after showing an extensive CPE were significantly higher than the viral titers from cells infected with virus alone, indicating that the delay of apoptosis by Z-VAD(OMe)-FMK extended the survival time of EPC cells, which lengthen the time for VHSV replication in the cells. In conclusion, Z-VAD(OMe)-FMK-mediated inhibition of apoptosis significantly increased the final titers of both wild-type VHSV and r

  19. Synthesis, Characterization, and In Vitro and In Vivo Evaluations of 4-(N-Docosahexaenoyl 2′, 2′-Difluorodeoxycytidine with Potent and Broad-Spectrum Antitumor Activity

    Directory of Open Access Journals (Sweden)

    Youssef W. Naguib

    2016-01-01

    Full Text Available In this study, a new compound, 4-(N-docosahexaenoyl 2′, 2′-difluorodeoxycytidine (DHA-dFdC, was synthesized and characterized. Its antitumor activity was evaluated in cell culture and in mouse models of pancreatic cancer. DHA-dFdC is a poorly soluble, pale yellow waxy solid, with a molecular mass of 573.3 Da and a melting point of about 96°C. The activation energy for the degradation of DHA-dFdC in an aqueous Tween 80–based solution is 12.86 kcal/mol, whereas its stability is significantly higher in the presence of vitamin E. NCI-60 DTP Human Tumor Cell Line Screening revealed that DHA-dFdC has potent and broad-spectrum antitumor activity, especially in leukemia, renal, and central nervous system cancer cell lines. In human and murine pancreatic cancer cell lines, the IC50 value of DHA-dFdC was up to 105-fold lower than that of dFdC. The elimination of DHA-dFdC in mouse plasma appeared to follow a biexponential model, with a terminal phase t1/2 of about 58 minutes. DHA-dFdC significantly extended the survival of genetically engineered mice that spontaneously develop pancreatic ductal adenocarcinoma. In nude mice with subcutaneously implanted human Panc-1 pancreatic tumors, the antitumor activity of DHA-dFdC was significantly stronger than the molar equivalent of dFdC alone, DHA alone, or the physical mixture of them (1:1, molar ratio. DHA-dFdC also significantly inhibited the growth of Panc-1 tumors orthotopically implanted in the pancreas of nude mice, whereas the molar equivalent dose of dFdC alone did not show any significant activity. DHA-dFdC is a promising compound for the potential treatment of cancers in organs such as the pancreas.

  20. The landscape of host transcriptional response programs commonly perturbed by bacterial pathogens: towards host-oriented broad-spectrum drug targets.

    Science.gov (United States)

    Kidane, Yared H; Lawrence, Christopher; Murali, T M

    2013-01-01

    The emergence of drug-resistant pathogen strains and new infectious agents pose major challenges to public health. A promising approach to combat these problems is to target the host's genes or proteins, especially to discover targets that are effective against multiple pathogens, i.e., host-oriented broad-spectrum (HOBS) drug targets. An important first step in the discovery of such drug targets is the identification of host responses that are commonly perturbed by multiple pathogens. In this paper, we present a methodology to identify common host responses elicited by multiple pathogens. First, we identified host responses perturbed by each pathogen using a gene set enrichment analysis of publicly available genome-wide transcriptional datasets. Then, we used biclustering to identify groups of host pathways and biological processes that were perturbed only by a subset of the analyzed pathogens. Finally, we tested the enrichment of each bicluster in human genes that are known drug targets, on the basis of which we elicited putative HOBS targets for specific groups of bacterial pathogens. We identified 84 up-regulated and three down-regulated statistically significant biclusters. Each bicluster contained a group of pathogens that commonly dysregulated a group of biological processes. We validated our approach by checking whether these biclusters correspond to known hallmarks of bacterial infection. Indeed, these biclusters contained biological process such as inflammation, activation of dendritic cells, pro- and anti- apoptotic responses and other innate immune responses. Next, we identified biclusters containing pathogens that infected the same tissue. After a literature-based analysis of the drug targets contained in these biclusters, we suggested new uses of the drugs Anakinra, Etanercept, and Infliximab for gastrointestinal pathogens Yersinia enterocolitica, Helicobacter pylori kx2 strain, and enterohemorrhagic Escherichia coli and the drug Simvastatin for

  1. The landscape of host transcriptional response programs commonly perturbed by bacterial pathogens: towards host-oriented broad-spectrum drug targets.

    Directory of Open Access Journals (Sweden)

    Yared H Kidane

    Full Text Available BACKGROUND: The emergence of drug-resistant pathogen strains and new infectious agents pose major challenges to public health. A promising approach to combat these problems is to target the host's genes or proteins, especially to discover targets that are effective against multiple pathogens, i.e., host-oriented broad-spectrum (HOBS drug targets. An important first step in the discovery of such drug targets is the identification of host responses that are commonly perturbed by multiple pathogens. RESULTS: In this paper, we present a methodology to identify common host responses elicited by multiple pathogens. First, we identified host responses perturbed by each pathogen using a gene set enrichment analysis of publicly available genome-wide transcriptional datasets. Then, we used biclustering to identify groups of host pathways and biological processes that were perturbed only by a subset of the analyzed pathogens. Finally, we tested the enrichment of each bicluster in human genes that are known drug targets, on the basis of which we elicited putative HOBS targets for specific groups of bacterial pathogens. We identified 84 up-regulated and three down-regulated statistically significant biclusters. Each bicluster contained a group of pathogens that commonly dysregulated a group of biological processes. We validated our approach by checking whether these biclusters correspond to known hallmarks of bacterial infection. Indeed, these biclusters contained biological process such as inflammation, activation of dendritic cells, pro- and anti- apoptotic responses and other innate immune responses. Next, we identified biclusters containing pathogens that infected the same tissue. After a literature-based analysis of the drug targets contained in these biclusters, we suggested new uses of the drugs Anakinra, Etanercept, and Infliximab for gastrointestinal pathogens Yersinia enterocolitica, Helicobacter pylori kx2 strain, and enterohemorrhagic Escherichia

  2. Characterisation of the Candida albicans Phosphopantetheinyl Transferase Ppt2 as a Potential Antifungal Drug Target.

    Directory of Open Access Journals (Sweden)

    Katharine S Dobb

    Full Text Available Antifungal drugs acting via new mechanisms of action are urgently needed to combat the increasing numbers of severe fungal infections caused by pathogens such as Candida albicans. The phosphopantetheinyl transferase of Aspergillus fumigatus, encoded by the essential gene pptB, has previously been identified as a potential antifungal target. This study investigated the function of its orthologue in C. albicans, PPT2/C1_09480W by placing one allele under the control of the regulatable MET3 promoter, and deleting the remaining allele. The phenotypes of this conditional null mutant showed that, as in A. fumigatus, the gene PPT2 is essential for growth in C. albicans, thus fulfilling one aspect of an efficient antifungal target. The catalytic activity of Ppt2 as a phosphopantetheinyl transferase and the acyl carrier protein Acp1 as a substrate were demonstrated in a fluorescence transfer assay, using recombinant Ppt2 and Acp1 produced and purified from E.coli. A fluorescence polarisation assay amenable to high-throughput screening was also developed. Therefore we have identified Ppt2 as a broad-spectrum novel antifungal target and developed tools to identify inhibitors as potentially new antifungal compounds.

  3. Triazole antifungals: a review.

    Science.gov (United States)

    Peyton, L R; Gallagher, S; Hashemzadeh, M

    2015-12-01

    Invasive fungal infections and systemic mycosis, whether from nosocomial infection or immunodeficiency, have been on an upward trend for numerous years. Despite advancements in antifungal medication, treatment in certain patients can still be difficult for reasons such as impaired organ function, limited administration routes or poor safety profiles of the available antifungal medications. The growing number of invasive fungal species becoming resistant to current antifungal medications is of appreciable concern. Triazole compounds containing one or more 1,2,4-triazole rings have been shown to contain some of the most potent antifungal properties. Itracon-azole and fluconazole were some of the first triazoles synthesized, but had limitations associated with their use. Second-generation triazoles such as voriconazole, posa-conazole, albaconazole, efinaconazole, ravuconazole and isavuconazole are all derivatives of either itraconazole or fluconazole, and designed to overcome the deficiencies of their parent drugs. The goal of this manuscript is to review antifungal agents derived from triazole.

  4. Proteinaceous toxins of Stagonospora nodorum, the causal agent of triticale leaf and glume blotch.

    Science.gov (United States)

    Walczewski, Jakub; Arseniuk, Edward

    2014-01-01

    S. nodorum is an economically important necrotrophic pathogen of cereals and grasses worldwide. In past several years appeared in literature quite a number of reports on existence of proteinaceous effectors produced by the fungus which induce necrosis in cereal host tissue. These host specific toxins induce necrosis by interacting with specific, dominant host genes. Up to the present research on S. nodorum toxin resistance was conducted only with wheat. Because wheat chromosomes are present in triticale genome, it is highly likely that mechanism used by S. nodorum for necrosis induction in triticale is the same as in wheat. Simple pilot experiment conducted in our laboratory, confirms that mechanism of necrosis induction via proteinaceous toxins is similar for both, wheat and triticale.

  5. Antifungal Compounds from Cyanobacteria

    Directory of Open Access Journals (Sweden)

    Tânia K. Shishido

    2015-04-01

    Full Text Available Cyanobacteria are photosynthetic prokaryotes found in a range of environments. They are infamous for the production of toxins, as well as bioactive compounds, which exhibit anticancer, antimicrobial and protease inhibition activities. Cyanobacteria produce a broad range of antifungals belonging to structural classes, such as peptides, polyketides and alkaloids. Here, we tested cyanobacteria from a wide variety of environments for antifungal activity. The potent antifungal macrolide scytophycin was detected in Anabaena sp. HAN21/1, Anabaena cf. cylindrica PH133, Nostoc sp. HAN11/1 and Scytonema sp. HAN3/2. To our knowledge, this is the first description of Anabaena strains that produce scytophycins. We detected antifungal glycolipopeptide hassallidin production in Anabaena spp. BIR JV1 and HAN7/1 and in Nostoc spp. 6sf Calc and CENA 219. These strains were isolated from brackish and freshwater samples collected in Brazil, the Czech Republic and Finland. In addition, three cyanobacterial strains, Fischerella sp. CENA 298, Scytonema hofmanni PCC 7110 and Nostoc sp. N107.3, produced unidentified antifungal compounds that warrant further characterization. Interestingly, all of the strains shown to produce antifungal compounds in this study belong to Nostocales or Stigonematales cyanobacterial orders.

  6. Antifungal compounds from cyanobacteria.

    Science.gov (United States)

    Shishido, Tânia K; Humisto, Anu; Jokela, Jouni; Liu, Liwei; Wahlsten, Matti; Tamrakar, Anisha; Fewer, David P; Permi, Perttu; Andreote, Ana P D; Fiore, Marli F; Sivonen, Kaarina

    2015-04-13

    Cyanobacteria are photosynthetic prokaryotes found in a range of environments. They are infamous for the production of toxins, as well as bioactive compounds, which exhibit anticancer, antimicrobial and protease inhibition activities. Cyanobacteria produce a broad range of antifungals belonging to structural classes, such as peptides, polyketides and alkaloids. Here, we tested cyanobacteria from a wide variety of environments for antifungal activity. The potent antifungal macrolide scytophycin was detected in Anabaena sp. HAN21/1, Anabaena cf. cylindrica PH133, Nostoc sp. HAN11/1 and Scytonema sp. HAN3/2. To our knowledge, this is the first description of Anabaena strains that produce scytophycins. We detected antifungal glycolipopeptide hassallidin production in Anabaena spp. BIR JV1 and HAN7/1 and in Nostoc spp. 6sf Calc and CENA 219. These strains were isolated from brackish and freshwater samples collected in Brazil, the Czech Republic and Finland. In addition, three cyanobacterial strains, Fischerella sp. CENA 298, Scytonema hofmanni PCC 7110 and Nostoc sp. N107.3, produced unidentified antifungal compounds that warrant further characterization. Interestingly, all of the strains shown to produce antifungal compounds in this study belong to Nostocales or Stigonematales cyanobacterial orders.

  7. Broad-spectrum Antibiotic Plus Metronidazole May Not Prevent the Deterioration of Necrotizing Enterocolitis From Stage II to III in Full-term and Near-term Infants: A Propensity Score-matched Cohort Study.

    Science.gov (United States)

    Luo, Li-Juan; Li, Xin; Yang, Kai-Di; Lu, Jiang-Yi; Li, Lu-Quan

    2015-10-01

    Necrotizing enterocolitis (NEC) is the most common and frequently dangerous neonatal gastrointestinal disease. Studies have shown broad-spectrum antibiotics plus anaerobic antimicrobial therapy did not prevent the deterioration of NEC among very low birth preterm infants. However, few studies about this therapy which focused on full-term and near-term infant with NEC has been reported. The aim of this study was to evaluate the effect of broad-spectrum antibiotic plus metronidazole in preventing the deterioration of NEC from stage II to III in full-term and near-term infants.A retrospective cohort study based on the propensity score (PS) 1:1 matching was performed among the full-term and near-term infants with NEC (Bell stage ≥II). All infants who received broad-spectrum antibiotics were divided into 2 groups: group with metronidazole treatment (metronidazole was used ≥4 days continuously, 15 mg/kg/day) and group without metronidazole treatment. The depraved rates of stage II NEC between the 2 groups were compared. Meanwhile, the risk factors associated with the deterioration of stage II NEC were analyzed by case-control study in the PS-matched cases.A total of 229 infants met the inclusion criteria. Before PS-matching, we found the deterioration of NEC rate in the group with metronidazole treatment was higher than that in the group without metronidazole treatment (18.1% [28/155] vs 8.1% [6/74]; P = 0.048). After PS-matching, 73 pairs were matched, and the depraved rate of NEC in the group with metronidazole treatment was not lower than that in the group without metronidazole treatment (15.1% vs 8.2%; P = 0.2). Binary logistic regression analysis showed that sepsis after NEC (odds ratio [OR] 3.748, 95% confidence interval [CI] 1.171-11.998, P = 0.03), the need to use transfusion of blood products after diagnosis of NEC (OR 8.003, 95% CI 2.365-27.087, P = 0.00), and the need of longer time for nasogastric suction were risk factors for stage II NEC progressing to

  8. Enhanced Antifungal Activity by Ab-Modified Amphotericin B-Loaded Nanoparticles Using a pH-Responsive Block Copolymer

    Science.gov (United States)

    Tang, Xiaolong; Dai, Jingjing; Xie, Jun; Zhu, Yongqiang; Zhu, Ming; Wang, Zhi; Xie, Chunmei; Yao, Aixia; Liu, Tingting; Wang, Xiaoyu; Chen, Li; Jiang, Qinglin; Wang, Shulei; Liang, Yong; Xu, Congjing

    2015-06-01

    Fungal infections are an important cause of morbidity and mortality in immunocompromised patients. Amphotericin B (AMB), with broad-spectrum antifungal activity, has long been recognized as a powerful fungicidal drug, but its clinical toxicities mainly nephrotoxicity and poor solubility limit its wide application in clinical practice. The fungal metabolism along with the host immune response usually generates acidity at sites of infection, resulting in loss of AMB activity in a pH-dependent manner. Herein, we developed pH-responsive AMB-loaded and surface charge-switching poly( d, l-lactic- co-glycolic acid)- b-poly( l-histidine)- b-poly(ethylene glycol) (PLGA-PLH-PEG) nanoparticles for resolving the localized acidity problem and enhance the antifungal efficacy of AMB. Moreover, we modified AMB-encapsulated PLGA-PLH-PEG nanoparticles with anti- Candida albicans antibody (CDA) (CDA-AMB-NPs) to increase the targetability. Then, CDA-AMB-NPs were characterized in terms of physical characteristics, in vitro drug release, stability, drug encapsulation efficiency, and toxicity. Finally, the targetability and antifungal activity of CDA-AMB-NPs were investigated in vitro /in vivo. The result demonstrated that CDA-AMB-NPs significantly improve the targetability and bioavailability of AMB and thus improve its antifungal activity and reduce its toxicity. These NPs may become a good drug carrier for antifungal treatment.

  9. Synthesis and biological evaluation of novel fluconazole analogues bearing 1,3,4-oxadiazole moiety as potent antifungal agents.

    Science.gov (United States)

    Liao, Jun; Yang, Fan; Zhang, Lei; Chai, Xiaoyun; Zhao, Qingjie; Yu, Shichong; Zou, Yan; Meng, Qingguo; Wu, Qiuye

    2015-04-01

    A novel series of fluconazole based mimics incorporating 1,3,4-oxadiazole moiety were designed and synthesized. All the title compounds were characterized by (1)H-NMR, (13)C-NMR, and Q-TOF-MS. Preliminary results revealed that most of analogues exhibited significant antifungal activity against seven pathogenic fungi. Compounds 9g and 9k (MIC80 ≤ 0.125 μg/mL, respectively) were found more potent than the positive controls itraconazole and fluconazole as broad-spectrum antifungal agents. The observed docking results showed that the 1,3,4-oxadiazole moiety enhanced the affinity binding to the cytochrome P450 14α-demethylase (CYP51).

  10. The chitin-binding capability of Cy-AMP1 from cycad is essential to antifungal activity.

    Science.gov (United States)

    Yokoyama, Seiya; Iida, Yuto; Kawasaki, Yousuke; Minami, Yuji; Watanabe, Keiichi; Yagi, Fumio

    2009-07-01

    Antimicrobial peptides are important components of the host innate immune responses by exerting broad-spectrum microbicidal activity against pathogenic microbes. Cy-AMP1 found in the cycad (Cycas revoluta) seeds has chitin-binding ability, and the chitin-binding domain was conserved in knottin-type and hevein-type antimicrobial peptides. The recombinant Cy-AMP1 was expressed in Escherichia coli and purified to study the role of chitin-binding domain. The mutants of Cy-AMP1 lost chitin-binding ability completely, and its antifungal activity was markedly decreased in comparison with native Cy-AMP1. However, the antimicrobial activities of the mutant peptides are nearly identical to that of native one. It was suggested that the chitin-binding domain plays an essential role in antifungal, but not antimicrobial, activity of Cy-AMP1.

  11. Antifungal pharmacokinetics and pharmacodynamics.

    Science.gov (United States)

    Lepak, Alexander J; Andes, David R

    2014-11-10

    Successful treatment of infectious diseases requires choice of the most suitable antimicrobial agent, comprising consideration of drug pharmacokinetics (PK), including penetration into infection site, pathogen susceptibility, optimal route of drug administration, drug dose, frequency of administration, duration of therapy, and drug toxicity. Antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) studies consider these variables and have been useful in drug development, optimizing dosing regimens, determining susceptibility breakpoints, and limiting toxicity of antifungal therapy. Here the concepts of antifungal PK/PD studies are reviewed, with emphasis on methodology and application. The initial sections of this review focus on principles and methodology. Then the pharmacodynamics of each major antifungal drug class (polyenes, flucytosine, azoles, and echinocandins) is discussed. Finally, the review discusses novel areas of pharmacodynamic investigation in the study and application of combination therapy.

  12. Sulfolobicins, Specific Proteinaceous Toxins Produced by Strains of the Extremely Thermophilic Archaeal Genus Sulfolobus

    Science.gov (United States)

    Prangishvili, David; Holz, Ingelore; Stieger, Evelyn; Nickell, Stephan; Kristjansson, Jakob K.; Zillig, Wolfram

    2000-01-01

    Several novel strains of “Sulfolobus islandicus” produced proteinaceous toxins, termed sulfolobicins, which killed cells of other strains of the same species, as well as of Sulfolobus solfataricus P1 and Sulfolobus shibatae B12, but not of the producer strains and of Sulfolobus acidocaldarius DSM639. The sulfolobicin purified from the strain HEN2/2 had a molecular mass of about 20 kDa. It was found to be associated with the producer cells as well as with cell-derived S-layer-coated spherical membrane vesicles 90 to 180 nm in diameter and was not released from the cells in soluble form. PMID:10781574

  13. Antifungal activity of diethyldithiocarbamate.

    Science.gov (United States)

    Allerberger, F; Reisinger, E C; Söldner, B; Dierich, M P

    1989-10-01

    Sodium diethyldithiocarbamate (DTC) was evaluated for its ability to combat four different species of fungi in vitro. Using a microtiter-broth-dilution method we were able to demonstrate an antifungal activity against Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus and Mucor mucedo in doses achievable by intravenous administration in man.

  14. 3-(3,4,5-Trimethoxybenzylidene)-2,4-pentanedione: Design of a novel photostabilizer with in vivo SPF boosting properties and its use in developing broad-spectrum sunscreen formulations.

    Science.gov (United States)

    Chaudhuri, R K; Ollengo, M A; Singh, P; Martincigh, B S

    2017-02-01

    The study concerned the synthesis of a novel photostabilizer based on benzylidenepentanedione chemistry and the evaluation of its potential in developing a broad-spectrum sunscreen formulation containing avobenzone. 3-(3,4,5-Trimethoxybenzylidene)-2-4-pentanedione (TMBP) was synthesized through a condensation reaction and incorporated into a sunscreen formulation containing, inter alia, avobenzone. The SPF, critical wavelength and in vitro photostability of the product were measured. The photostability was compared with that afforded by current avobenzone photostabilizers, namely octocrylene, ethylhexylmethoxycrylene and diethylhexylsyringylidenemalonate. The photostability of TMBP either alone or in the presence of avobenzone in a methanolic solution was also evaluated by UV spectrophotometric and HPLC analyses. The optical properties of TMBP were estimated experimentally and supported by time-dependent density functional theory (TD-DFT) calculations. The ability of TMBP to stabilize avobenzone under ultraviolet (UV) light exposure was shown both in formulated products and in solution. A comparative stability study incorporating various combinations of avobenzone, TMBP (vs. three commercial photostabilizers) and UVB sunscreens clearly showed TMBP to be a very effective stabilizer. The photostabilizing effect of TMBP arises from triplet-state energy transfer from avobenzone to TMBP and through light-induced reactions that preserve the main chromophores. Interestingly, a 50% in vivo SPF boosting was observed when TMBP was used with organic and inorganic sunscreens when alone it has no contribution to SPF. TMBP-containing sunscreen formulations clearly showed a critical wavelength of well over 370 nm and can thus be categorized as broad-spectrum sunscreens. We were able to design a very effective photostabilizer, trimethoxybenzylidene pentanedione (INCI name), based on benzylidenepentanedione chemistry. TMBP is very efficient in stabilizing avobenzone in formulated

  15. Identification of proteinaceous binders used in artworks by MALDI-TOF mass spectrometry.

    Science.gov (United States)

    Kuckova, Stepanka; Hynek, Radovan; Kodicek, Milan

    2007-05-01

    Proper identification of proteinaceous binders in artworks is essential for specification of the painting technique and thus also for selection of the restoration method; moreover, it might be helpful for the authentication of the artwork. This paper is concerned with the optimisation of analysis of the proteinaceous binders contained in the colour layers of artworks. Within this study, we worked out a method for the preparation and analysis of solid samples from artworks using tryptic cleavage and subsequent analysis of the acquired peptide mixture by matrix-assisted laser desorption/ionisation time of flight mass spectrometry. To make this approach rational and efficient, we created a database of commonly used binders (egg yolk, egg white, casein, milk, curd, whey, gelatine, and various types of animal glues); certain peaks in the mass spectra of these binders, formed by rich protein mixtures, were matched to amino acid sequences of the individual proteins that were found in the Internet database ExPASy; their cleavage was simulated by the program Mass-2.0-alpha4. The method developed was tested on model samples of ground layers prepared by an independent laboratory and then successfully applied to a real sample originating from a painting by Edvard Munch.

  16. Analysis of renal cyst of high density containing proteinaceous fluid: report of 6 cases

    Institute of Scientific and Technical Information of China (English)

    Jin Wen; Han zhong Li; He Xiao

    2008-01-01

    Objective:To investigate clinical features and imageology of renal cysts of high density, containing proteinaceous fluid and increase the diagnosis and treatment level of this special type renal cyst. Methods:Six cases were proven to be renal cysts of high density(pathologically) from 2002 to 2007 were reviewed. Among 6 cases, 1 was in the upper pole of kidney, 4 were medial and 1 was located in the anus perineum. All were 2-5 cm in size. Ultrasonography(US) excretory unognaphy, multiphase CT and renal angiography DSA imaging was performed for preoperative diagnosis. The preoperative diagnosis found renal neoplasms in 4 and renal cysts in 2. All of them were operated by partial nephrectomy. Results:All of the 6 renal high density renal masses were reseoted surgically, which were proved pathologically to be renal cysts; high density present. All of them contained proteinaceous fluid with benign cyst walls on histologic examination. No recurrence was seen in any of these cases during a long follow-up. Conclusion:CT and B-US have a higher diagnostic value, which can show the internal shape and character better. B-US or CT guided puncturing biopsy can be better applied to atypical renal cysts. Once the correct diagnosis is acquired, laparoscopic surgical treatment should be carried out.

  17. In vitro production and antifungal activity of peptide ABP-dHC-cecropin A.

    Science.gov (United States)

    Zhang, Jiaxin; Movahedi, Ali; Xu, Junjie; Wang, Mengyang; Wu, Xiaolong; Xu, Chen; Yin, Tongming; Zhuge, Qiang

    2015-04-10

    The antimicrobial peptide ABP-dHC-cecropin A is a small cationic peptide with potent activity against a wide range of bacterial species. Evidence of antifungal activity has also been suggested; however, testing of this peptide has been limited due to the low expression of cecropin proteins in Escherichia coli. To improve expression of this peptide in E. coli, ABP-dHC-cecropin A was cloned into a pSUMO vector and transformed into E. coli, resulting in the production of a pSUMO-ABP-dHC-cecropin A fusion protein. The soluble form of this protein was then purified by Ni-IDA chromatography, yielding a total of 496-mg protein per liter of fermentation culture. The SUMO-ABP-dHC-cecropin A fusion protein was then cleaved using a SUMO protease and re-purified by Ni-IDA chromatography, yielding a total of 158-mg recombinant ABP-dHC-cecropin A per liter of fermentation culture at a purity of ≥94%, the highest yield reported to date. Antifungal activity assays performed using this purified recombinant peptide revealed strong antifungal activity against both Candida albicans and Neurospora crassa, as well as Rhizopus, Fusarium, Alternaria, and Mucor species. Combined with previous analyses demonstrating strong antibacterial activity against a number of important bacterial pathogens, these results confirm the use of ABP-dHC-cecropin A as a broad-spectrum antimicrobial peptide, with significant therapeutic potential.

  18. Sensitivity of Candida albicans to essential oils: are they an alternative to antifungal agents?

    Science.gov (United States)

    Bona, E; Cantamessa, S; Pavan, M; Novello, G; Massa, N; Rocchetti, A; Berta, G; Gamalero, E

    2016-12-01

    Candida albicans is an important opportunistic pathogen, responsible for the majority of yeast infections in humans. Essential oils, extracted from aromatic plants, are well-known antimicrobial agents, characterized by a broad spectrum of activities, including antifungal properties. The aim of this work was to assess the sensitivity of 30 different vaginal isolated strains of C. albicans to 12 essential oils, compared to the three main used drugs (clotrimazole, fluconazole and itraconazole). Thirty strains of C. albicans were isolated from vaginal swab on CHROMagar(™) Candida. The agar disc diffusion method was employed to determine the sensitivity to the essential oils. The antifungal activity of the essential oils and antifungal drugs (clotrimazole, itraconazole and fluconazole) were investigated using a microdilution method. Transmission and scanning electron microscopy analyses were performed to get a deep inside on cellular damages. Mint, basil, lavender, tea tree oil, winter savory and oregano essential oils inhibited both the growth and the activity of C. albicans more efficiently than clotrimazole. Damages induced by essential oils at the cellular level were stronger than those caused by clotrimazole. Candida albicans is more sensitive to different essential oils compared to the main used drugs. Moreover, the essential oil affected mainly the cell wall and the membranes of the yeast. The results of this work support the research for new alternatives or complementary therapies against vaginal candidiasis. © 2016 The Society for Applied Microbiology.

  19. Antifungal activity of diketopiperazines and stilbenes against plant pathogenic fungi in vitro.

    Science.gov (United States)

    Kumar, S Nishanth; Nambisan, Bala

    2014-01-01

    The present study aimed to investigate antifungal activity of a stilbene and diketopiperazine compounds against plant pathogenic fungi, including Phytophthora capsici, P. colocasiae, Botrytis cinerea and Colletotrichum gloeosporioides. Minimal inhibition concentrations (MIC) and minimal fungicidal concentrations (MFC) of stilbenes and diketopiperazines for each fungus were determined using microplate method. Best activity was recorded by stilbenes against P. capsici and P. colocasiae. All four test compounds were effective in inhibiting different stages of the life cycle of test fungi. Stilbenes were more effective than diketopiperazines in inhibiting mycelial growth and inhibiting different stages of the life cycle of P. capsici and P. colocasiae. Rupture of released zoospores induced by stilbenes was reduced by addition of 100 mM glucose. The effects of stilbenes on mycelial growth and zoospore release, but not zoospore rupture, were reduced largely when pH value was above 7. In addition, stilbenes were investigated for its antifungal stability against Phytophthora sp. The results showed that stilbenes maintained strong fungistatic activity over a wide pH range (pH 4–9) and temperature range (70–120 °C). The compound stilbenes exhibited strong and stable broad-spectrum antifungal activity, and had a significant fungicidal effect on fungal cells. Results from prebiocontrol evaluations performed to date are probably useful in the search for alternative approaches to controlling serious plant pathogens.

  20. Antifungal Activity of 14-Helical β-Peptides against Planktonic Cells and Biofilms of Candida Species

    Directory of Open Access Journals (Sweden)

    Namrata Raman

    2015-08-01

    Full Text Available Candida albicans is the most prevalent cause of fungal infections and treatment is further complicated by the formation of drug resistant biofilms, often on the surfaces of implanted medical devices. In recent years, the incidence of fungal infections by other pathogenic Candida species such as C. glabrata, C. parapsilosis and C. tropicalis has increased. Amphiphilic, helical β-peptide structural mimetics of natural antimicrobial α-peptides have been shown to exhibit specific planktonic antifungal and anti-biofilm formation activity against C. albicans in vitro. Here, we demonstrate that β-peptides are also active against clinically isolated and drug resistant strains of C. albicans and against other opportunistic Candida spp. Different Candida species were susceptible to β-peptides to varying degrees, with C. tropicalis being the most and C. glabrata being the least susceptible. β-peptide hydrophobicity directly correlated with antifungal activity against all the Candida clinical strains and species tested. While β-peptides were largely ineffective at disrupting existing Candida biofilms, hydrophobic β-peptides were able to prevent the formation of C. albicans, C. glabrata, C. parapsilosis and C. tropicalis biofilms. The broad-spectrum antifungal activity of β-peptides against planktonic cells and in preventing biofilm formation suggests the promise of this class of molecules as therapeutics.

  1. Secretive Expression of Insect Antifungal Peptide-Encoded Genes in Pichia pastoris and Activity Assay of the Products

    Institute of Scientific and Technical Information of China (English)

    SANG Yan-xia; DENG Xiao-juan; YANG Wan-ying; WANG Wen-xian; WEN Shuo-yang; LIU Wen-quan; HUANG Ya-dong; CAO Yang

    2007-01-01

    The antifungal peptides, drosomycin (Drs) and its isoform drosomycin-like C (Drs-lC) from Drosophila melanogaster and Thanatin from Podisus maculiventris, have potent activity with broad spectrum against filamentous fungi. Secretive expression of these genes in yeasts makes it possible to utilize the supernatants of yeast culture as protective reagents on fruit, vegetable, food and other agricultural products. So the study of effective secretion by yeast expression system is of great importance. Three genes, Drs, Drs-lC, and Thanatin, were cloned into pPICZαA and the recombinant vectors,pPICZαA-Drs, pPICZαA-Drs-IC, and pPICZαA-Thanatin were transformed into Pichia pastoris by the electric transfer method. The recombinant P. pastoris, which was screened by phenotype selection and PCR amplification, wasinduced to express antifungal peptide by methanol. The expressive products of the three recombinants showed antifungal activity against 5 out of 6 test fungi strains, and the products of Thanatin also had strong activity against the tested bacteria. The three antifungal peptide genes, Drs, Drs-lC, and Thanatin, were constructed into yeast P. pastoris. The expressed peptides were successfully secreted into the culture medium and exhibited potent activities against the test strains.

  2. Proteinaceous inhibitors of carbohydrate-active enzymes in cereals: implication in agriculture, cereal processing and nutrition

    DEFF Research Database (Denmark)

    Juge, N.; Svensson, Birte

    2006-01-01

    Enzymes that degrade, modify, or create glycosidic bonds are involved in carbohydrate biosynthesis and remodelling. Microbial carbohydrate-active enzymes form the basis of current green technology in the food, feed, starch, paper and pulp industries and the revolution in genomics may offer long......-term gains on the quality and quantity of the raw materials. Proteinaceous inhibitors of carbohydrate-active enzymes (alpha-amylase, limit-dextrinase, polygalacturonase, pectin lyase, pectin methylesterase, invertase and xyloglucan endoglucanase) naturally occur in plants where they are involved in various...... roles from plant defence to metabolism. Xylanase inhibitors represent the latest addition to this growing family. In this review, we will focus on the inhibitors of carbohydrate-active enzymes present in cereals, mostly represented by et-amylase and xylanase inhibitors, and summarise the existing...

  3. Study on performance of submerged membrane bioreactor in proteinaceous wastewater treatment

    Institute of Scientific and Technical Information of China (English)

    Zhang Ying; Ren Nanqi; Liu Xiaolei; Chen Zhaobo

    2005-01-01

    The continuous flowing experiment using a submerged membrane bioreactor (SMBR) in proteinaceous wastewater treatment was studied. The removal rate of the chemical oxygen demand (COD) was over 96.0% and the biochemical oxygen demand (BOD) was above 98.1%,the average removal rate of the total nitrogen (TN) was 61.7%,the removal rate of NH3-N was as high as 99%,but the removal effect of the total phosphorus (TP) was instable. The analysis under the condition of our experiments came to the conclusion that backwashing, waterpower scouring, low-pressure operation and control of mixed liquor suspended solid (MLSS) could lighten the attenuation of filtration flux in SMBR.

  4. Structural analysis of proteinaceous components in Byssal threads of the mussel Mytilus galloprovincialis.

    Science.gov (United States)

    Hagenau, Anja; Scheidt, Holger A; Serpell, Louise; Huster, Daniel; Scheibel, Thomas

    2009-02-11

    The mussel byssus is a unique holdfast structure employed by marine mussels to colonize diverse substrates. The byssus consists of extracellular threads with mainly proteinaceous components. Individual threads reveal high tensile strength at their distal end and high elasticity in their proximal portion. Our studies show that proteins of the distal part are oriented along the thread axis and are well-ordered with a high beta-structural content. In contrast, proteins of the proximal part are less ordered and are not as well-oriented with primarily alpha-helical structure. The detected differences in the structural features of the proteins along a byssus thread are likely an important basis for its gradual mechanical properties.

  5. Vv-AMP1, a ripening induced peptide from Vitis vinifera shows strong antifungal activity

    Directory of Open Access Journals (Sweden)

    Vivier Melané A

    2008-07-01

    Full Text Available Abstract Background Latest research shows that small antimicrobial peptides play a role in the innate defense system of plants. These peptides typically contribute to preformed defense by developing protective barriers around germinating seeds or between different tissue layers within plant organs. The encoding genes could also be upregulated by abiotic and biotic stimuli during active defense processes. The peptides display a broad spectrum of antimicrobial activities. Their potent anti-pathogenic characteristics have ensured that they are promising targets in the medical and agricultural biotechnology sectors. Results A berry specific cDNA sequence designated Vv-AMP1, Vitis vinifera antimicrobial peptide 1, was isolated from Vitis vinifera. Vv-AMP1 encodes for a 77 amino acid peptide that shows sequence homology to the family of plant defensins. Vv-AMP1 is expressed in a tissue specific, developmentally regulated manner, being only expressed in berry tissue at the onset of berry ripening and onwards. Treatment of leaf and berry tissue with biotic or abiotic factors did not lead to increased expression of Vv-AMP1 under the conditions tested. The predicted signal peptide of Vv-AMP1, fused to the green fluorescent protein (GFP, showed that the signal peptide allowed accumulation of its product in the apoplast. Vv-AMP1 peptide, produced in Escherichia coli, had a molecular mass of 5.495 kDa as determined by mass spectrometry. Recombinant Vv-AMP1 was extremely heat-stable and showed strong antifungal activity against a broad spectrum of plant pathogenic fungi, with very high levels of activity against the wilting disease causing pathogens Fusarium oxysporum and Verticillium dahliae. The Vv-AMP1 peptide did not induce morphological changes on the treated fungal hyphae, but instead strongly inhibited hyphal elongation. A propidium iodide uptake assay suggested that the inhibitory activity of Vv-AMP1 might be associated with altering the membrane

  6. Vv-AMP1, a ripening induced peptide from Vitis vinifera shows strong antifungal activity

    Science.gov (United States)

    de Beer, Abré; Vivier, Melané A

    2008-01-01

    Background Latest research shows that small antimicrobial peptides play a role in the innate defense system of plants. These peptides typically contribute to preformed defense by developing protective barriers around germinating seeds or between different tissue layers within plant organs. The encoding genes could also be upregulated by abiotic and biotic stimuli during active defense processes. The peptides display a broad spectrum of antimicrobial activities. Their potent anti-pathogenic characteristics have ensured that they are promising targets in the medical and agricultural biotechnology sectors. Results A berry specific cDNA sequence designated Vv-AMP1, Vitis vinifera antimicrobial peptide 1, was isolated from Vitis vinifera. Vv-AMP1 encodes for a 77 amino acid peptide that shows sequence homology to the family of plant defensins. Vv-AMP1 is expressed in a tissue specific, developmentally regulated manner, being only expressed in berry tissue at the onset of berry ripening and onwards. Treatment of leaf and berry tissue with biotic or abiotic factors did not lead to increased expression of Vv-AMP1 under the conditions tested. The predicted signal peptide of Vv-AMP1, fused to the green fluorescent protein (GFP), showed that the signal peptide allowed accumulation of its product in the apoplast. Vv-AMP1 peptide, produced in Escherichia coli, had a molecular mass of 5.495 kDa as determined by mass spectrometry. Recombinant Vv-AMP1 was extremely heat-stable and showed strong antifungal activity against a broad spectrum of plant pathogenic fungi, with very high levels of activity against the wilting disease causing pathogens Fusarium oxysporum and Verticillium dahliae. The Vv-AMP1 peptide did not induce morphological changes on the treated fungal hyphae, but instead strongly inhibited hyphal elongation. A propidium iodide uptake assay suggested that the inhibitory activity of Vv-AMP1 might be associated with altering the membrane permeability of the fungal

  7. Broad-Spectrum Solution-Processed Photovoltaics

    Science.gov (United States)

    Ip, Alexander Halley

    High global demand for energy coupled with dwindling fossil fuel supply has driven the development of sustainable energy sources such as solar photovoltaics. Emerging solar technologies aim for low-cost, solution-processable materials which would allow wide deployment. Colloidal quantum dots (CQDs) are such a materials system which exhibits the ability to absorb across the entire solar spectrum, including in the infrared where many technologies cannot harvest photons. However, due to their nanocrystalline nature, CQDs are susceptible to surface-associated electronic traps which greatly inhibit performance. In this thesis, surface engineering of CQDs is presented through a combined ligand approach which improves the passivation of surface trap states. A metal halide treatment is found to passivate quantum dot surfaces in solution, while bifunctional organic ligands produce a dense film in solid state. This approach reduced midgap trap states fivefold compared with conventional passivation strategies and led to solar cells with a record certified 7.0% power conversion efficiency. The effect of this process on the electronic structure is studied through photoelectron spectroscopy. It is found that while the halide provides deep trap passivation, the nature of the metal cation on the CQD surface affects the density of band tail states. This effect is explored further through a wide survey of materials, and it is found that the coordination ability of the metal cation is responsible for the suppression of shallow traps. With this understanding of CQD surface passivation, broad spectral usage is then explored through a study of visible-absorbing organolead halide perovskite materials as well as narrow-bandgap CQD solar cells. Control over growth conditions and modification of electrode interfaces resulted in efficient perovskite devices with effective usages of visible photons. For infrared-absorbing CQDs, it is found that, in addition to providing surface trap passivation, ligands must be used to prevent nanocrystal fusion that leads to introduction of band tail states. The most efficient solution-processed infrared solar cells yet reported are achieved through this approach, opening a path towards low-cost photovoltaics with high spectral usage.

  8. A Fluorescent Broad-Spectrum Proteasome Inhibitor

    NARCIS (Netherlands)

    Verdoes, Martijn; Florea, Bogdan I.; Menendez-Benito, Victoria; Maynard, Christa J.; Witte, Martin D.; Linden, Wouter A. van der; Nieuwendijk, Adrianus M.C.H. van den; Hofmann, Tanja; Berkers, Celia R.; Leeuwen, Fijs W.B. van; Groothuis, Tom A.; Leeuwenburgh, Michiel A.; Ovaa, Huib; Neefjes, Jacques J.; Filippov, Dmitri V.; Marel, Gijs A. van der; Dantuma, Nico P.; Overkleeft, Herman S.

    2006-01-01

    The proteasome is an essential evolutionary conserved protease involved in many regulatory systems. Here, we describe the synthesis and characterization of the activity-based, fluorescent, and cell-permeable inhibitor Bodipy TMR-Ahx3L3VS (MV151), which specifically targets all active subunits of the

  9. Ceftobiprole: a new broad spectrum cephalosporin.

    Science.gov (United States)

    El Solh, Ali

    2009-07-01

    Ceftobiprole, formerly designated BAL9141/Ro 63-9141, is a pyrrolidinone-3-ylidene-methyl cephalosporin with demonstrated in vitro activity against MRSA, Enterococcus faecalis, Enterobacteriaceae and Pseudomonas aeruginosa. Ceftobiprole has a low potential for inducing chromosomal AmpC beta-lactamases but it is hydrolyzed by most extended spectrum beta-lactamases and metallo-beta-lactamases. Glomerular filtration is predominantly responsible for removal of the free drug from the systemic circulation. The efficacy of ceftobiprole in the treatment of complicated skin and ski-structure infections has been recently demonstrated in two Phase III randomized clinical trials involving 1600 patients. Two other Phase III clinical trials to assess ceftobiprole's efficacy in community-acquired pneumonia and nosocomial pneumonia have also concluded. While the drug met the noninferiority criteria for community-acquired pneumonia and nosocomial pneumonia involving non-ventilator associated pneumonia, ceftobiprole was less effective than the comparator in ventilator associated pneumonia subjects. Ceftobiprole was well tolerated with a safety profile consistent with the cephalosporin class of antibiotic. The most frequent drug-related adverse event was dysgeusia. Ceftobiprole is intended for use in the hospital for the treatment of infections that frequently involve beta-lactam-resistant Gram-negative and Gram-positive organisms.

  10. Antifungal adjuvants: Preserving and extending the antifungal arsenal.

    Science.gov (United States)

    Butts, Arielle; Palmer, Glen E; Rogers, P David

    2017-02-17

    As the rates of systemic fungal infections continue to rise and antifungal drug resistance becomes more prevalent, there is an urgent need for new therapeutic options. This issue is exacerbated by the limited number of systemic antifungal drug classes. However, the discovery, development, and approval of novel antifungals is an extensive process that often takes decades. For this reason, there is growing interest and research into the possibility of combining existing therapies with various adjuvants that either enhance activity or overcome existing mechanisms of resistance. Reports of antifungal adjuvants range from plant extracts to repurposed compounds, to synthetic peptides. This approach would potentially prolong the utility of currently approved antifungals and mitigate the ongoing development of resistance.

  11. Antifungal activity of rimocidin and a new rimocidin derivative BU16 produced by Streptomyces mauvecolor BU16 and their effects on pepper anthracnose.

    Science.gov (United States)

    Jeon, B J; Kim, J D; Han, J W; Kim, B S

    2016-05-01

    The objective of this study was to explore antifungal metabolites targeting fungal cell envelope and to evaluate the control efficacy against anthracnose development in pepper plants. A natural product library comprising 3000 microbial culture extracts was screened via an adenylate kinase (AK)-based cell lysis assay to detect antifungal metabolites targeting the cell envelope of plant-pathogenic fungi. The culture extract of Streptomyces mauvecolor strain BU16 displayed potent AK-releasing activity. Rimocidin and a new rimocidin derivative, BU16, were identified from the extract as active constituents. BU16 is a tetraene macrolide containing a six-membered hemiketal ring with an ethyl group side chain instead of the propyl group in rimocidin. Rimocidin and BU16 showed broad-spectrum antifungal activity against various plant-pathogenic fungi and demonstrated potent control efficacy against anthracnose development in pepper plants. Antifungal metabolites produced by S. mauvecolor strain BU16 were identified to be rimocidin and BU16. The compounds displayed potent control efficacy against pepper anthracnose. Rimocidin and BU16 would be active ingredients of disease control agents disrupting cell envelope of plant-pathogenic fungi. The structure and antifungal activity of rimocidin derivative BU16 is first described in this study. © 2016 The Society for Applied Microbiology.

  12. 3C和3CL蛋白酶及广谱抑制剂的研究进展%Broad spectrum inhibitors of 3C and 3CL proteases:research advances

    Institute of Scientific and Technical Information of China (English)

    张启燕; 张文会; 肖军海; 李松

    2016-01-01

    Picornaviruses(PV)and coronaviruses(CoV) are positive-stranded RNA viruses. Pathogens in the family can cause hand,foot and mouth disease,myocarditis, common cold ,severe respiratory and intestinal diseases. 3C and 3CL proteases, belonging to cysteine proteases,are required to process polyproteins into mature proteins for viral replication,which plays an impor⁃tant role in viral replication because substrate binding sites are highly conservative and have similar catalytic mechanism. 3C and 3CL proteases are different from protease in the human body ,which represents a promising anti-viral drug target. Using 3C and 3CL pro⁃teinase structural similarities,broad spectrum protease inhibitors have been found successfully. This review describes recent develop⁃ments of broad spectrum protease inhibitors targeting on 3C and 3CL proteases,and briefly illustrates the mechanism of the inhibitors, which may benefit to the development of virus therapy.%小RNA病毒和冠状病毒属于单正链RNA病毒,其家族中的病原体易导致手足口病、心肌炎、普通感冒以及严重的呼吸道和肠道疾病。3C和3CL蛋白酶都属于半胱氨酸蛋白酶,底物结合位点高度保守且具有相似的催化机制,是催化单正链RNA病毒前体蛋白裂解的关键蛋白酶,对病毒的复制有重要作用。人体中没有与其相似的蛋白酶,是目前广谱抗单正链RNA病毒研究的重要靶点。利用3C和3CL蛋白酶结构的相同点,成功发现了具有广谱作用的蛋白酶抑制剂。本文简要概述3C和3CL蛋白酶的结构、功能和广谱抑制剂的研究进展,并简要阐释抑制剂的作用机制,对该类酶的广谱抑制剂研究和相关病毒的治疗具有指导意义。

  13. Improving qPCR methodology for detection of foaming bacteria by analysis of broad-spectrum primers and a highly specific probe for quantification of Nocardia spp. in activated sludge.

    Science.gov (United States)

    Asvapathanagul, P; Olson, B H

    2017-01-01

    To develop qPCR broad-spectrum primers combined with a Nocardia genus-specific probe for the identification of a broad spectrum of Nocardia spp. and to analyse the effects of using this developed primer and probe set on the ability to quantify Nocardia spp. in mixed DNA. The consequences of using a degenerative primer set and species-specific probe for the genus Nocardia on qPCR assays were examined using DNA extracts of pure cultures and activated sludge. The mixed DNA extracts where the target organism Nocardia flavorosea concentration ranged from 5 × 10(2) to 5 × 10(6) copies per reaction, while the background organism's DNA (Mycobacterium bovis) concentration was held at 5 × 10(6) copies per reaction, only produced comparable cycle threshold florescence levels when N. flavorosea concentration was greater than or equal to the background organism concentration. When concentrations of N. flavorosea were lowered in increments of 1 log, while holding M. bovis concentrations constant at 5 × 10(6) copies per reaction, all assays demonstrated delayed cycle threshold values with a maximum 34·6-fold decrease in cycle threshold at a ratio of 10(6) M. bovis: 10(2) N. flavorosea copies per reaction. The data presented in this study indicated that increasing the ability of a primer set to capture a broad group of organisms can affect the accuracy of quantification even when a highly specific probe is used. This study examined several applications of molecular tools in complex communities such as evaluating the effect of mispriming vs interference. It also elucidates the importance of understanding the community genetic make-up on primer design. Degenerative primers are very useful in amplifying bacterial DNA across genera, but reduce the efficiency of qPCR reactions. Therefore, standards that address closely related background species must be used to obtain accurate qPCR results. © 2016 The Society for Applied Microbiology.

  14. Thailandins A and B, New Polyene Macrolactone Compounds Isolated from Actinokineospora bangkokensis Strain 44EHW(T), Possessing Antifungal Activity against Anthracnose Fungi and Pathogenic Yeasts.

    Science.gov (United States)

    Intra, Bungonsiri; Greule, Anja; Bechthold, Andreas; Euanorasetr, Jirayut; Paululat, Thomas; Panbangred, Watanalai

    2016-06-29

    Two new polyene macrolactone antibiotics, thailandins A, 1, and B, 2, were isolated from the fermentation broth of rhizosphere soil-associated Actinokineospora bangkokensis strain 44EHW(T). The new compounds from this strain were purified using semipreparative HPLC and Sephadex LH-20 gel filtration while following an antifungal activity guided fractionation. Their structures were elucidated through spectroscopic techniques including UV, HR-ESI-MS, and NMR. These compounds demonstrated broad spectrum antifungal activity against fungi causing anthracnose disease (Colletotrichum gloeosporioides DoA d0762, Colletotrichum gloeosporiodes DoA c1060, and Colletotrichum capsici DoA c1511) as well as pathogenic yeasts (Candida albicans MT 2013/1, Candida parasilopsis DKMU 434, and Cryptococcus neoformans MT 2013/2) with minimum inhibitory concentrations ranging between 16 and 32 μg/mL. This is the first report of polyene antibiotics produced by Actinokineospora species as bioactive compounds against anthracnose fungi and pathogenic yeast strains.

  15. Antifungal therapy in European hospitals

    DEFF Research Database (Denmark)

    Zarb, P; Amadeo, B; Muller, A;

    2012-01-01

    respiratory (19.2%) and gastrointestinal (18.8%). The most used antifungal was fluconazole (60.5%) followed by caspofungin (10.5%). Antifungal-antibacterial combinations were frequently used (77.5%). The predominance of fluconazole use in participating hospitals could result in an increase in prevalence...

  16. Optimization for the production of surfactin with a new synergistic antifungal activity.

    Directory of Open Access Journals (Sweden)

    Xiangyang Liu

    Full Text Available BACKGROUND: Two of our long term efforts are to discover compounds with synergistic antifungal activity from metabolites of marine derived microbes and to optimize the production of the interesting compounds produced by microorganisms. In this respect, new applications or mechanisms of already known compounds with a high production yield could be continually identified. Surfactin is a well-known lipopeptide biosurfactant with a broad spectrum of antimicrobial and antiviral activity; however, there is less knowledge on surfactin's antifungal activity. In this study, we investigated the synergistic antifungal activity of C(15-surfactin and the optimization of its production by the response surface method. METHODOLOGY/PRINCIPAL FINDINGS: Using a synergistic antifungal screening model, we found that the combination of C(15-surfactin and ketoconazole (KTC showed synergistic antifungal effect on Candida albicans SC5314 when the concentrations of C(15-surfactin and KTC were 6.25 µg/mL and 0.004 µg/mL, respectively. These concentrations were lower than their own efficient antifungal concentrations, which are >100 µg/mL and 0.016 µg/mL, respectively. The production of C(15-surfactin from Bacillus amyloliquefaciens was optimized by the response surface methodology in shaker flask cultivation. The Plackett-Burman design found sucrose, ammonium nitrate and NaH(2PO(4 x 2H(2O to have significant effects on C(15-surfactin production. The optimum values of the tested variables were 21.17 g/L sucrose, 2.50 g/L ammonium nitrate and 11.56 g/L NaH(2PO(4·2H(2O. A production of 134.2 mg/L, which were in agreement with the prediction, was observed in a verification experiment. In comparison to the production of original level (88.6 mg/L, a 1.52-fold increase had been obtained. CONCLUSION/SIGNIFICANCE: This work first found that C(15-surfactin was an efficient synergistic antifungal agent, and demonstrated that response surface methodology was an effective method

  17. Caspofungin as antifungal prophylaxis in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis

    Directory of Open Access Journals (Sweden)

    Döring Michaela

    2012-07-01

    Full Text Available Abstract Background Pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT often receive intravenous liposomal amphotericin B (L-AmB as antifungal prophylaxis. There are no guidelines for antifungal prophylaxis in children in this situation. Caspofungin (CAS, a broad-spectrum echinocandin, could be an effective alternative with lower nephrotoxicity than L-AmB. Methods We retrospectively analyzed the safety, feasibility, and efficacy of CAS in our center, and compared the results with L-AmB as antifungal monoprophylaxis in pediatric patients undergoing HSCT. 60 pediatric patients received L-AmB (1 or 3 mg/kg bw/day and another 60 patients received CAS (50 mg/m2/day as antifungal monoprophylaxis starting on day one after HSCT. The median ages of patients receiving L-AmB and CAS were 7.5 years and 9.5 years, respectively. Results No proven breakthrough fungal infection occurred in either group during the median treatment period of 23 days in the L-AmB group and 24 days in the CAS group. One patient receiving CAS developed probable invasive aspergillosis. During L-AmB treatment, potassium levels significantly decreased below normal values. Patients treated with L-AmB had more drug-related side effects and an increased need for oral supplementation with potassium, sodium bicarbonate and calcium upon discharge as compared with the CAS group. CAS was well-tolerated and safe in this cohort of immunocompromised pediatric patients, who underwent high-dose chemotherapy and HSCT. Conclusion Prophylactic CAS and L-AmB showed similar efficacy in this biggest cohort of pediatric patients after allogeneic HSCT reported, so far. A prospective randomized trial in children is warranted to allow for standardized guidelines.

  18. Chalcone derivatives as potential antifungal agents: Synthesis, and antifungal activity

    Directory of Open Access Journals (Sweden)

    Deepa Gupta

    2015-01-01

    Full Text Available Much research has been carried out with the aim to discover the therapeutic values of chalcone derivatives. Chalcones possess wide range of pharmacological activity such as antibacterial, antimalarial, antiprotozoal, antitubercular, anticancer, and antifungal agents etc. The presence of reactive α,β-unsaturated keto group in chalcones is found to be responsible for their biological activity. The rapid developments of resistance to antifungal agents, led to design, and synthesize the new antifungal agents. The derivatives of chalcones were prepared using Claisen-Schmidt condensation scheme with appropriate tetralone and aldehyde derivatives. Ten derivatives were synthesized and were biologically screened for antifungal activity. The newly synthesized derivatives of chalcone showed antifungal activity against fungal species, Microsporum gypseum. The results so obtained were superior or comparable to ketoconazole. It was observed that none of the compounds tested showed positive results for fungi Candida albicans nor against fungi Aspergillus niger. Chalcone derivatives showed inhibitory effect against M. gypseum species of fungus. It was found that among the chalcone derivatives so synthesized, two of them, that is, 4-chloro derivative, and unsubstituted derivative of chalcone showed antifungal activity superior to ketoconazole. Thus, these can be the potential new molecule as antifungal agent.

  19. Kaposi sarcoma-associated herpes virus targets the lymphotactin receptor with both a broad spectrum antagonist vCCL2 and a highly selective and potent agonist vCCL3

    DEFF Research Database (Denmark)

    Lüttichau, Hans R; Johnsen, Anders H; Jurlander, Jesper;

    2007-01-01

    Large DNA viruses such as herpesvirus and poxvirus encode proteins that target and exploit the chemokine system of their host. These proteins have the potential to block or change the orchestrated recruitment of leukocytes to sites of viral infection. The genome of Kaposi sarcoma-associated herpes...... virus (KSHV) encodes three chemokine-like proteins named vCCL1, vCCL2, and vCCL3. In this study vCCL3 was probed in parallel with vCCL1 and vCCL2 against a panel of the 18 classified human chemokine receptors. In calcium mobilization assays vCCL1 acted as a selective CCR8 agonist, whereas vCCL2...... was found to act as a broad spectrum chemokine antagonist of human chemokine receptors, including the lymphotactin receptor. In contrast vCCL3 was found to be a highly selective agonist for the human lymphotactin receptor XCR1. The potency of vCCL3 was found to be 10-fold higher than the endogenous human...

  20. Phylloseptin-PBa—A Novel Broad-Spectrum Antimicrobial Peptide from the Skin Secretion of the Peruvian Purple-Sided Leaf Frog (Phyllomedusa Baltea Which Exhibits Cancer Cell Cytotoxicity

    Directory of Open Access Journals (Sweden)

    Yuantai Wan

    2015-12-01

    Full Text Available Antimicrobial peptides from amphibian skin secretion display remarkable broad-spectrum antimicrobial activity and are thus promising for the discovery of new antibiotics. In this study, we report a novel peptide belonging to the phylloseptin family of antimicrobial peptides, from the skin secretion of the purple-sided leaf frog, Phyllomedusa baltea, which was named Phylloseptin-PBa. Degenerate primers complementary to putative signal peptide sites of frog skin peptide precursor-encoding cDNAs were designed to interrogate a skin secretion-derived cDNA library from this frog. Subsequently, the peptide was isolated and identified using reverse phase HPLC and MS/MS fragmentation. The synthetic replicate was demonstrated to have activity against S. aureus, E. coli and C. albicans at concentrations of 8, 128 and 8 mg/L, respectively. In addition, it exhibited anti-proliferative activity against the human cancer cell lines, H460, PC3 and U251MG, but was less active against a normal human cell line (HMEC. Furthermore, a haemolysis assay was performed to assess mammalian cell cytotoxicity of Phylloseptin-PBa. This peptide contained a large proportion of α-helical domain, which may explain its antimicrobial and anticancer activities.

  1. Structure activity relationship of C-2 ether substituted 1,5-naphthyridine analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-5).

    Science.gov (United States)

    Singh, Sheo B; Kaelin, David E; Meinke, Peter T; Wu, Jin; Miesel, Lynn; Tan, Christopher M; Olsen, David B; Lagrutta, Armando; Fukuda, Hideyuki; Kishii, Ryuta; Takei, Masaya; Takeuchi, Tomoko; Takano, Hisashi; Ohata, Kohei; Kurasaki, Haruaki; Nishimura, Akinori; Shibata, Takeshi; Fukuda, Yasumichi

    2015-09-01

    Oxabicyclooctane linked novel bacterial topoisomerase inhibitors (NBTIs) are new class of recently reported broad-spectrum antibacterial agents. They target bacterial DNA gyrase and topoisomerase IV and bind to a site different than quinolones. They show no cross-resistance to known antibiotics and provide opportunity to combat drug-resistant bacteria. A structure activity relationship of the C-2 substituted ether analogs of 1,5-naphthyridine oxabicyclooctane-linked NBTIs are described. Synthesis and antibacterial activities of a total of 63 analogs have been summarized representing alkyl, cyclo alkyl, fluoro alkyl, hydroxy alkyl, amino alkyl, and carboxyl alkyl ethers. All compounds were tested against three key strains each of Gram-positive and Gram-negative bacteria as well as for hERG binding activities. Many key compounds were also tested for the functional hERG activity. Six compounds were evaluated for efficacy in a murine bacteremia model of Staphylococcus aureus infection. Significant tolerance for the ether substitution (including polar groups such as amino and carboxyl) at C-2 was observed for S. aureus activity however the same was not true for Enterococcus faecium and Gram-negative strains. Reduced clogD generally showed reduced hERG activity and improved in vivo efficacy but was generally associated with decreased overall potency. One of the best compounds was hydroxy propyl ether (16), which mainly retained the potency, spectrum and in vivo efficacy of AM8085 associated with the decreased hERG activity and improved physical property.

  2. Novel pyrazolo[3,4-d]pyrimidine with 4-(1H-benzimidazol-2-yl)-phenylamine as broad spectrum anticancer agents: Synthesis, cell based assay, topoisomerase inhibition, DNA intercalation and bovine serum albumin studies.

    Science.gov (United States)

    Singla, Prinka; Luxami, Vijay; Singh, Raja; Tandon, Vibha; Paul, Kamaldeep

    2017-01-27

    A series of new pyrazolo[3,4-d]pyrimidine possessing 4-(1H-benzimidazol-2-yl)-phenylamine moiety at C4 position and primary as well as secondary amines at C6 position has been designed and synthesized. Their antitumor activities were evaluated against a panel of 60 human cancer cell lines at National Cancer Institute (NCI). Six compounds displayed potent and broad spectrum anticancer activities at 10 μM. Compounds 8, 12, 14 and 17 proved to be the most active and efficacious candidate in this series, with mean GI50 values of 1.30 μM, 1.43 μM, 2.38 μM and 2.18 μM, respectively against several cancer cell lines. Further biological evaluation of these compounds suggested that these compounds induce apoptosis and inhibit human topoisomerase (Topo) IIα as a possible intracellular target. UV-visible and fluorescence studies of these compounds revealed strong interaction with ct-DNA and bovine serum albumin (BSA).

  3. Novel, broad-spectrum anticonvulsants containing a sulfamide group: pharmacological properties of (S)-N-[(6-chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]sulfamide (JNJ-26489112).

    Science.gov (United States)

    McComsey, David F; Smith-Swintosky, Virginia L; Parker, Michael H; Brenneman, Douglas E; Malatynska, Ewa; White, H Steve; Klein, Brian D; Wilcox, Karen S; Milewski, Michael E; Herb, Mark; Finley, Michael F A; Liu, Yi; Lubin, Mary Lou; Qin, Ning; Reitz, Allen B; Maryanoff, Bruce E

    2013-11-27

    Broad-spectrum anticonvulsants are of considerable interest as antiepileptic drugs, especially because of their potential for treating refractory patients. Such "neurostabilizers" have also been used to treat other neurological disorders, including migraine, bipolar disorder, and neuropathic pain. We synthesized a series of sulfamide derivatives (4-9, 10a-i, 11a, 11b, 12) and evaluated their anticonvulsant activity. Thus, we identified promising sulfamide 4 (JNJ-26489112) and explored its pharmacological properties. Compound 4 exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures. Mechanistically, 4 inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels and was effective as a K(+) channel opener. The anticonvulsant profile of 4 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. On the basis of its pharmacology and other favorable characteristics, 4 was advanced into human clinical studies.

  4. Comparison of nitroethane, 2-nitro-1-propanol, lauric acid, Lauricidin® and the Hawaiian marine algae, Chaetoceros, for potential broad-spectrum control of anaerobically grown lactic acid bacteria.

    Science.gov (United States)

    Božic, Aleksandar K; Anderson, Robin C; Ricke, Steven C; Crandall, Philip G; O'Bryan, Corliss A

    2012-01-01

    The gastrointestinal tract of bovines often contains bacteria that contribute to disorders of the rumen, and may also contain foodborne or opportunistic human pathogens as well as bacteria capable of causing mastitis in cows. Thus there is a need to develop broad-spectrum therapies that are effective while not leading to unacceptably long antibiotic withdrawal times. The effects of the CH(4)-inhibitors nitroethane (2 mg/mL), 2-nitro-1-propanol (2 mg/mL), lauric acid (5 mg/mL), the commercial product Lauricidin® (5 mg/mL), and a finely ground product of the Hawaiian marine algae, Chaetoceros (10 mg/mL), were compared in pure cultures of Streptococcus agalactia, Enterococcus faecium, Streptococcus bovis, and in a mixed lactic acid rumen bacterial culture. Lauricidin® and lauric acid exhibited the most bactericidal acidity against all bacteria. These results suggest potential animal health benefits from supplementing cattle diets with lauric acid or Lauricidin® to improve the health of the rumen and help prevent shedding of human pathogens.

  5. Novel, Broad-Spectrum Anticonvulsants Containing a Sulfamide Group: Pharmacological Properties of (S)-N-[(6-Chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]sulfamide (JNJ-26489112)

    Science.gov (United States)

    McComsey, David F.; Smith-Swintosky, Virginia L.; Parker, Michael H.; Brenneman, Douglas E.; Malatynska, Ewa; White, H. Steve; Klein, Brian D.; Wilcox, Karen S.; Milewski, Michael E.; Herb, Mark; Finley, Michael F. A.; Liu, Yi; Lubin, Mary Lou; Qin, Ning; Reitz, Allen B.; Maryanoff, Bruce E.

    2014-01-01

    Broad-spectrum anticonvulsants are of considerable interest as antiepileptic drugs, especially because of their potential for treating refractory patients. Such “neurostabilizers” have also been used to treat other neurological disorders, including migraine, bipolar disorder, and neuropathic pain. We synthesized a series of sulfamide derivatives (4–9, 10a–i, 11a, 11b, 12) and evaluated their anticonvulsant activity. Thus, we identified promising sulfamide 4 (JNJ-26489112) and explored its pharmacological properties. Compound 4 exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically-induced, and chemically-induced seizures. Mechanistically, 4 inhibited voltage-gated Na+ channels and N-type Ca2+ channels, and was effective as a K+ channel opener. The anticonvulsant profile of 4 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. On the basis of its pharmacology and other favorable characteristics, 4 was advanced into human clinical studies. PMID:24205976

  6. Co-option and evolution of non-olfactory proteinaceous pheromones in a terrestrial lungless salamander.

    Science.gov (United States)

    Doty, Kari A; Wilburn, Damien B; Bowen, Kathleen E; Feldhoff, Pamela W; Feldhoff, Richard C

    2016-03-01

    Gene co-option is a major force in the evolution of novel biological functions. In plethodontid salamanders, males deliver proteinaceous courtship pheromones to the female olfactory system or transdermally to the bloodstream. Molecular studies identified three families of highly duplicated, rapidly evolving pheromones (PRF, PMF, and SPF). Analyses for Plethodon salamanders revealed pheromone mixtures of primarily PRF and PMF. The current study demonstrates that in Desmognathus ocoee--a plesiomorphic species with transdermal delivery--SPF is the major pheromone component representing >30% of total protein. Chromatographic profiles of D. ocoee pheromones were consistent from May through October. LC/MS-MS analysis suggested uniform SPF isoform expression between individual male D. ocoee. A gene ancestry for SPF with the Three-Finger Protein superfamily was supported by intron-exon boundaries, but not by the disulfide bonding pattern. Further analysis of the pheromone mixture revealed paralogs to peptide hormones that contained mutations in receptor binding regions, such that these novel molecules may alter female physiology by acting as hormone agonists/antagonists. Cumulatively, gene co-option, duplication, and neofunctionalization have permitted recruitment of additional gene families for pheromone activity. Such independent co-option events may be playing a key role in salamander speciation by altering male traits that influence reproductive success. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Analysis of proteinaceous components of the organic matrix of endoskeletal sclerites from the alcyonarian Lobophytum crassum.

    Science.gov (United States)

    Rahman, M Azizur; Isa, Y; Takemura, A; Uehara, T

    2006-03-01

    The mesoglea of alcyonarians is occupied by an abundance of minute calcitic sclerites. The sclerites of the alcyonarian Lobophytum crassum contain a water-soluble organic matrix comprising 0.48% of the sclerite weight and a water-insoluble fraction comprising 1.15% of the sclerite weight. Analysis of proteinaceous components in the soluble fraction shows a particularly high content of aspartic acid, followed by alanine, glycine, and glutamate. Aspartic acid, glycine, alanine, and glutamate are the most abundant residues in the insoluble fraction. In both cases, the fractions show the highest concentration of aspartic acid from the total proteins. In an in vitro assay, we show that the matrix proteins extracted from the calcitic sclerites induce the formation of amorphous calcium carbonate prior to its transformation into the calcitic crystalline form. We also show scanning electron micrographs of the rhombohedral calcite crystals used as template, the protein imprinted with these crystals. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of both matrices shows the protein fractions at 67 and 48 kDa. The soluble matrix shows two additional faint bands. Both fractions stain for a carbohydrate at 67 kDa, indicating a glycoprotein at this molecular weight. A newly derived protein sequence was subjected to bioinformatics analysis involving identification of similarities to other acidic proteins. The identification of these proteins in alcyonarian endoskeletal sclerites emphasizes the fundamental importance of such acidic proteins and sheds more light on the functions of these proteins in the processes of biocalcification.

  8. Characterization of the proteinaceous skeletal organic matrix from the precious coral Corallium konojoi.

    Science.gov (United States)

    Rahman, M Azizur; Karl, Kristian; Nonaka, Masanori; Fujimura, Hiroyuki; Shinjo, Ryuichi; Oomori, Tamotsu; Wörheide, Gert

    2014-11-01

    The Japanese red and pink corals are known to be precious because of their commercial value resulting from their use in ornaments, jewelry, and medicine. Precious corals are very interesting models for biomineralization studies and possess two different skeletal structures: an axial skeleton and an endoskeleton (sclerites). Although it has long been known that the organic matrix proteins existing in coral skeletons are critical for the oriented precipitation of CaCO3 crystals, these proteins in moderate deep-sea Japanese precious corals remain uncharacterized. Therefore, in this study, we performed skeletal whole proteome analyses using 1D and 2D electrophoresis, nano-LC, and MALDI-TOF-TOF MS. We identified a total of 147 functional coral skeletal organic matrix proteins (120 from the sclerites and 36 from the axial skeleton), including two calcium-binding calmodulin. Among the organic matrix proteins identified, nine key proteins are highly typical and common in both skeletons. Strong glycosylation activity, which is essential for skeletal formation in calcifying organisms, was detected in both skeletons. This work demonstrates unique biomineralization-related proteins in precious corals and provides the first description of the major proteinaceous components of CaCO3 minerals in precious corals, enabling the comparative investigation of biocalcification in other octocorals.

  9. Late Holocene variations in Pacific surface circulation and biogeochemistry inferred from proteinaceous deep-sea corals

    Directory of Open Access Journals (Sweden)

    T. P. Guilderson

    2013-09-01

    Full Text Available δ15N and δ13C data obtained from samples of proteinaceous deep-sea corals collected from the North Pacific Subtropical Gyre (Hawaiian Archipelago and the central equatorial Pacific (Line Islands document multidecadal to century-scale variability in the isotopic composition of surface-produced particulate organic matter exported to the deep sea. Comparison of the δ13C data, where Line Islands samples are 0.6‰ more positive than the Hawaiian samples, supports the contention that the North Pacific Subtropical Gyre is more efficient than the tropical upwelling system at trapping and/or recycling nutrients within the mixed layer. δ15N values from the Line Islands samples are also more positive than those from the central gyre, and within the Hawaiian samples there is a gradient with more positive δ15N values in samples from the main Hawaiian Islands versus the French Frigate Shoals in the Northwestern Hawaiian Islands. The gradient in the Hawaiian samples likely reflects the relative importance of algal acquisition of metabolic N via dissolved seawater nitrate uptake versus nitrogen fixation. The Hawaiian sample set also exhibits a strong decrease in δ15N values from the mid-Holocene to present. We hypothesize that this decrease is most likely the result of decreasing trade winds, and possibly a commensurate decrease in entrainment of more positive δ15N-NO3 subthermocline water masses.

  10. A Nonpolycationic Fully Proteinaceous Multiagent System for Potent Targeted Delivery of siRNA

    Science.gov (United States)

    Liu, David V; Yang, Nicole J; Wittrup, K Dane

    2014-01-01

    Protein-based methods of targeted short-interfering RNA (siRNA) delivery have the potential to solve some of the problems faced by nanoparticle-based methods, such as poor pharmacokinetics and biodistribution, low tumor penetration, and polydispersity. However, protein-based targeted delivery has been limited to fusion proteins with polycationic peptides as siRNA carriers, whose high charge density in some cases results in undesirable biophysical and in vivo properties. Here, we present a fully proteinaceous, multiagent approach for targeted siRNA delivery to epidermal growth factor receptor (EGFR), using a nonpolycationic carrier for siRNA. Each agent contributes a fundamentally different mechanism of action that work together for potent targeted RNA interference. The first agent is an EGFR-targeted fusion protein that uses a double-stranded RNA-binding domain as a nonpolycationic siRNA carrier. This double-stranded RNA-binding domain fusion protein can deliver siRNA to the endosomes of an EGFR-expressing cell line. A second agent delivers the cholesterol-dependent cytolysin, perfringolysin O, in a targeted manner, which enhances the endosomal escape of siRNA and induces gene silencing. A third agent that clusters EGFR increases gene-silencing potency and decreases cytolysin toxicity. Altogether, this system is potent, with only 16 nmol/l siRNA required for gene silencing and a therapeutic window that spans two orders of magnitude of targeted cytolysin concentrations. PMID:24825362

  11. Particle contamination of parenteralia and in-line filtration of proteinaceous drugs.

    Science.gov (United States)

    Werner, Benjamin Patrick; Winter, Gerhard

    2015-12-30

    Protein drug products play an important role in the treatment of severe diseases. However, due to the instability of these complex molecules, protein aggregates can form which can compromise drug safety and efficacy including immunogenic reactions. In-line filtration during the administration of these drugs can serve as a final safeguarding step to protect patients from risks associated with proteinaceous particles. A unique analysis of more than 300 marketed protein drug products revealed that already around 16% of all these products are filtered during preparation or administration. Further, the research revealed that no standardized filtration practice exists. Broad variances regarding filter membrane or pore size are found and sometimes no specifications are mentioned at all. The benefits as well as possible negative impacts of filtration like filter shedding, extractables or drug adsorption are critically assessed. Several proposals to improve the current filtration practice and to expand the number of in-line filtered protein drug products are made. The suggestions include the demand for the specific usage of one filter membrane type, the establishment of a filtration routine for unfiltered protein drugs and a statistical analysis between filtered and non-filtered products with similar formulations to identify possible differences in the immunogenicity rate.

  12. Synthesis of Azole-containing Piperazine Derivatives and Evaluation of their Antibacterial, Antifungal and Cytotoxic Activities

    Energy Technology Data Exchange (ETDEWEB)

    Gan, Lin Ling; Fang, Bo; Zhou, Cheng He [Southwest University, Chongqing (China)

    2010-12-15

    A series of azole-containing piperazine derivatives have been designed and synthesized. The obtained compounds were investigated in vitro for their antibacterial, antifungal and cytotoxic activities. The preliminary results showed that most compounds exhibited moderate to significant antibacterial and antifungal activities in vitro. 1-(4-((4-chlorophenyl) (phenyl)methyl)piperazin-1-yl)-2-(1H-imidazol-1-yl)ethanone and 1-(4-((4-Chlorophenyl)(phenyl)methyl)piperazin-1- yl)-2-(2-phenyl-1H-imidazol-1-yl)ethanone gave remarkable and broad-spectrum antimicrobial efficacy against all tested strains with MIC values ranging from 3.1 to 25 μg/mL, and exhibited comparable activities to the standard drugs chloramphenicol and fluconazole in clinic. Moreover, 2-((4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)methyl)- 1H-benzo[d]imidazole was found to be the most effective in vitro against the PC-3 cell line, reaching growth inhibition values (36.4, 60.1 and 76.5%) for each tested concentration: 25 μM, 50 μM and 100 μM in dose-dependent manner. The results also showed that the azole ring had noticeable effect on their antimicrobial and cytotoxic activities, and imidazole and benzimidazole moiety were much more favourable to biological activity than 1,2,4-triazole.

  13. Fungal infections in marrow transplant recipients under antifungal prophylaxis with fluconazole

    Directory of Open Access Journals (Sweden)

    Oliveira J.S.R.

    2002-01-01

    Full Text Available Fungal infection is one of the most important causes of morbidity and mortality in bone marrow transplant (BMT recipients. The growing incidence of these infections is related to several factors including prolonged granulocytopenia, use of broad-spectrum antibiotics, conditioning regimens, and use of immunosuppression to avoid graft-versus-host disease (GvHD. In the present series, we report five cases of invasive mold infections documented among 64 BMT recipients undergoing fluconazole antifungal prophylaxis: 1 A strain of Scedosporium prolificans was isolated from a skin lesion that developed on day +72 after BMT in a chronic myeloid leukemic patient. 2 Invasive pulmonary aspergillosis (Aspergillus fumigatus was diagnosed on day +29 in a patient with a long period of hospitalization before being transplanted for severe aplastic anemia. 3 A tumoral lung lesion due to Rhizopus arrhizus (zygomycosis was observed in a transplanted patient who presented severe chronic GvHD. 4 A tumoral lesion due to Aspergillus spp involving the 7th, 8th and 9th right ribs and local soft tissue was diagnosed in a BMT patient on day +110. 5 A patient with a history of Ph1-positive acute lymphocytic leukemia exhibited a cerebral lesion on day +477 after receiving a BMT during an episode of severe chronic GvHD. At that time, blood and spinal fluid cultures yielded Fusarium sp. Opportunistic infections due to fungi other than Candida spp are becoming a major problem among BMT patients receiving systemic antifungal prophylaxis with fluconazole.

  14. A single Streptomyces symbiont makes multiple antifungals to support the fungus farming ant Acromyrmex octospinosus.

    Directory of Open Access Journals (Sweden)

    Ryan F Seipke

    Full Text Available Attine ants are dependent on a cultivated fungus for food and use antibiotics produced by symbiotic Actinobacteria as weedkillers in their fungus gardens. Actinobacterial species belonging to the genera Pseudonocardia, Streptomyces and Amycolatopsis have been isolated from attine ant nests and shown to confer protection against a range of microfungal weeds. In previous work on the higher attine Acromyrmex octospinosus we isolated a Streptomyces strain that produces candicidin, consistent with another report that attine ants use Streptomyces-produced candicidin in their fungiculture. Here we report the genome analysis of this Streptomyces strain and identify multiple antibiotic biosynthetic pathways. We demonstrate, using gene disruptions and mass spectrometry, that this single strain has the capacity to make candicidin and multiple antimycin compounds. Although antimycins have been known for >60 years we report the sequence of the biosynthetic gene cluster for the first time. Crucially, disrupting the candicidin and antimycin gene clusters in the same strain had no effect on bioactivity against a co-evolved nest pathogen called Escovopsis that has been identified in ∼30% of attine ant nests. Since the Streptomyces strain has strong bioactivity against Escovopsis we conclude that it must make additional antifungal(s to inhibit Escovopsis. However, candicidin and antimycins likely offer protection against other microfungal weeds that infect the attine fungal gardens. Thus, we propose that the selection of this biosynthetically prolific strain from the natural environment provides A. octospinosus with broad spectrum activity against Escovopsis and other microfungal weeds.

  15. A single Streptomyces symbiont makes multiple antifungals to support the fungus farming ant Acromyrmex octospinosus.

    Science.gov (United States)

    Seipke, Ryan F; Barke, Jörg; Brearley, Charles; Hill, Lionel; Yu, Douglas W; Goss, Rebecca J M; Hutchings, Matthew I

    2011-01-01

    Attine ants are dependent on a cultivated fungus for food and use antibiotics produced by symbiotic Actinobacteria as weedkillers in their fungus gardens. Actinobacterial species belonging to the genera Pseudonocardia, Streptomyces and Amycolatopsis have been isolated from attine ant nests and shown to confer protection against a range of microfungal weeds. In previous work on the higher attine Acromyrmex octospinosus we isolated a Streptomyces strain that produces candicidin, consistent with another report that attine ants use Streptomyces-produced candicidin in their fungiculture. Here we report the genome analysis of this Streptomyces strain and identify multiple antibiotic biosynthetic pathways. We demonstrate, using gene disruptions and mass spectrometry, that this single strain has the capacity to make candicidin and multiple antimycin compounds. Although antimycins have been known for >60 years we report the sequence of the biosynthetic gene cluster for the first time. Crucially, disrupting the candicidin and antimycin gene clusters in the same strain had no effect on bioactivity against a co-evolved nest pathogen called Escovopsis that has been identified in ∼30% of attine ant nests. Since the Streptomyces strain has strong bioactivity against Escovopsis we conclude that it must make additional antifungal(s) to inhibit Escovopsis. However, candicidin and antimycins likely offer protection against other microfungal weeds that infect the attine fungal gardens. Thus, we propose that the selection of this biosynthetically prolific strain from the natural environment provides A. octospinosus with broad spectrum activity against Escovopsis and other microfungal weeds.

  16. Molecular cloning, recombinant expression, and antifungal functional characterization of the lipid transfer protein from Panax ginseng.

    Science.gov (United States)

    Cai, Kexin; Wang, Jiawen; Wang, Min; Zhang, Hui; Wang, Siming; Zhao, Yu

    2016-07-01

    To establish an efficient expression system for a fusion protein GST-pgLTP (Lipid Transfer Protein) and to test its antifungal activity. The nucleotide sequence of LTP gene was obtained from Panax ginseng using RT-PCR. The ORF of the cDNA is 363 bp, codING for a protein OF 120 amino acids with a calculated MW of 12.09 kDa. The pgLTP gene with a His6-tag at the C-terminus was cloned into the pGEX-6p1 vector to generate a GST-fusion pgLTP protein construct that was expressed in Escherichia coli Rosetta. Following purification by Ni-NTA, the fusion protein exhibited antifungal activity against five fungi found in ginseng. The fusion protein GST-pgLTP has activity against a broad spectrum of phytopathogenic fungi, and can potentially be adapted for production to combat fungal diseases that affect P. ginseng.

  17. Microdilution in vitro antifungal susceptibility of Exophiala dermatitidis, a systemic opportunist.

    Science.gov (United States)

    Badali, H; de Hoog, G S; Sudhadham, M; Meis, J F

    2011-11-01

    The in vitro activities of eight antifungal agents were determined against clinical (n = 63 genotype A, n = 3 genotype B) and environmental (n = 2 genotype A, n = 13 genotype B) strains of Exophiala dermatitidis. The resulting MIC(90)s for all strains (N = 81) were, in increasing order, as follows: posaconazole, 0.125 μg/ml; itraconazole, 0.25 μg/ml; voriconazole, 0.5 μg/ml; amphotericin B, 0.5 μg/ml; isavuconazole, 1 μ/ml; caspofungin, 8 μg/ml; anidulafungin, 8 μg/ml and fluconazole, 16 μg/ml. There were no significant differences in the patterns of susceptibility between genotypes A and B, environmental and clinical strains, isolates recovered from cutaneous and deep locations and strains from different geographical areas (P > 0.05). The difference in the MIC(90)s between each of these groups was not more than one dilution. The present study demonstrated that, based on in vitro activity, posaconazole and itraconazole have the highest activity against this fungus. In addition, voriconazole and the experimental broad-spectrum antifungal triazole, isavuconazole, both of which are available as intravenous preparations, have adequate activity against E. dermatitidis. However, in vivo efficacy remains to be determined.

  18. Investigations on the Antifungal Effect of Nerol against Aspergillus flavus Causing Food Spoilage

    Directory of Open Access Journals (Sweden)

    Jun Tian

    2013-01-01

    Full Text Available The antifungal efficacy of nerol (NEL has been proved against Aspergillus flavus by using in vitro and in vivo tests. The mycelial growth of A. flavus was completely inhibited at concentrations of 0.8 μL/mL and 0.1 μL/mL NEL in the air at contact and vapor conditions, respectively. The NEL also had an evident inhibitory effect on spore germination in A. flavus along with NEL concentration as well as time-dependent kinetic inhibition. The NEL presented noticeable inhibition on dry mycelium weight and synthesis of aflatoxin B1 (AFB1 by A. flavus, totally restraining AFB1 production at 0.6 μL/mL. In real food system, the efficacy of the NEL on resistance to decay development in cherry tomatoes was investigated in vivo by exposing inoculated and control fruit groups to NEL vapor at different concentration. NEL vapors at 0.1 μL/mL air concentration significantly reduced artificially contaminated A. flavus and a broad spectrum of fungal microbiota. Results obtained from presented study showed that the NEL had a great antifungal activity and could be considered as a benefit and safe tool to control food spoilage.

  19. 不同品种香蕉内生菌分离及广谱拮抗菌的筛选%Endophytes Isolation and Broad-spectrum Antagonistic Bacterias Screening from Banana

    Institute of Scientific and Technical Information of China (English)

    王梦颖; 周登博; 井涛; 胡一凤; 高祝芬; 谢晴宜; 张锡炎; 戚春林

    2014-01-01

    In order to determine the main distribution of endophytes and their broad-spectrum antimicrobial activity, endophytes were obtained from healthy and diseased tissues of two disease-resistant and one disease susceptible banana cultivars. Endophytes were separated from roots, corms, pseudostems, leaves and store in the ultra-low on Luria-Bertani(LB), Yeast Extract with supplements(YE), and Potato Dextrose Agar(PDA)strain store medium. Then screened broad-spectrum antagonistic bacteria which against Fusarium oxysporum f. sp. Cubense, Curvularia lunata, Curvularia fallax, Corynespora cassiicola(Berk&Curt)Wei, Alternaria musae, Deightoniella troulosa, Colletotrichum musae, Pestalogiopsis sp., Btoryosphaeria dothidea. Taxonomy identification of 041, 04-1, 19-1, 03A-1 was conducted by evaluating morphologic characteristics and 16S rDNA gene sequences for phylogenetic analysis. After purification, total of 438 endophytes were obtained. The total of isolates showed that we obtained 240 strains bacteria, followed by 142 strains actinomycetes, and 56 strains fungi. The richest number of endophytes that isolated from diseased NanTian banana cultivars(128). Ten actinomyces and two bacterias were determined to possess antibiotic activity against Ten banana pathogens. Isolates 041 was the most effective and had 28.13±1.89 mm width of inhibition zone. Isolated 041, 04-1, 19-1, 034-1 were identified as Streptomyces misionensis.%旨在探究抗病品种与易感品种香蕉的健康株和病株内生菌与其中广谱拮抗菌的主要分布规律,并对广谱拮抗菌进行拮抗活性的测定。以样品根、球茎、假茎、叶为材料分离培养内生菌,在实验室条件下,筛选对供试的10种香蕉致病菌均有良好拮抗活性的菌株并测定它们的拮抗活性,对活性最强的菌株进行形态学、16S rDNA序列同源性分析。结果显示,分离得到内生菌438株,其中细菌240株,放线菌142株,真菌56株。抗病品种南天

  20. Posaconazole exhibits in vitro and in vivo synergistic antifungal activity with caspofungin or FK506 against Candida albicans.

    Directory of Open Access Journals (Sweden)

    Ying-Lien Chen

    Full Text Available The object of this study was to test whether posaconazole, a broad-spectrum antifungal agent inhibiting ergosterol biosynthesis, exhibits synergy with the β-1,3 glucan synthase inhibitor caspofungin or the calcineurin inhibitor FK506 against the human fungal pathogen Candida albicans. Although current drug treatments for Candida infection are often efficacious, the available antifungal armamentarium may not be keeping pace with the increasing incidence of drug resistant strains. The development of drug combinations or novel antifungal drugs to address emerging drug resistance is therefore of general importance. Combination drug therapies are employed to treat patients with HIV, cancer, or tuberculosis, and has considerable promise in the treatment of fungal infections like cryptococcal meningitis and C. albicans infections. Our studies reported here demonstrate that posaconazole exhibits in vitro synergy with caspofungin or FK506 against drug susceptible or resistant C. albicans strains. Furthermore, these combinations also show in vivo synergy against C. albicans strain SC5314 and its derived echinocandin-resistant mutants, which harbor an S645Y mutation in the CaFks1 β-1,3 glucan synthase drug target, suggesting potential therapeutic applicability for these combinations in the future.

  1. Antifungal and antiaflatoxigenic properties of Cuminum cyminum (L.) seed essential oil and its efficacy as a preservative in stored commodities.

    Science.gov (United States)

    Kedia, Akash; Prakash, Bhanu; Mishra, Prashant K; Dubey, N K

    2014-01-03

    The study reports potential of Cuminum cyminum (cumin) seed essential oil (EO) as a plant based shelf life enhancer against fungal and aflatoxin contamination and lipid peroxidation. The EO showed efficacy as a preservative in food systems (stored wheat and chickpeas). A total of 1230 fungal isolates were obtained from food samples, with Aspergillus flavus LHP(C)-D6 identified as the highest aflatoxin producer. Cumin seed EO was chemically characterized through GC-MS where cymene (47.08%) was found as the major component. The minimum inhibitory concentration and minimum aflatoxin inhibitory concentration of EO were 0.6 and 0.5 μl/ml respectively. The EO showed toxicity against a broad spectrum of food borne fungi. The antifungal action of EO on ergosterol content in the plasma membrane of A. flavus was determined. The EO showed strong antioxidant potential having IC50 0.092 μl/ml. As a fumigant in food systems, the EO provided sufficient protection of food samples against fungal association without affecting seed germination. In view of the antifungal and antiaflatoxigenic nature, free radical scavenging potential and efficacy in food system, cumin seed EO may be able to provide protection of food commodities against quantitative and qualitative losses, thereby enhancing their shelf life. The present investigation comprises the first report on antifungal mode of action of cumin seed EO and its efficacy as fumigant in food systems.

  2. Third generation cephalosporin resistant Enterobacteriaceae and multidrug resistant gram-negative bacteria causing bacteremia in febrile neutropenia adult cancer patients in Lebanon, broad spectrum antibiotics use as a major risk factor, and correlation with poor prognosis

    Directory of Open Access Journals (Sweden)

    Rima eMoghnieh

    2015-02-01

    Full Text Available Bacteremia remains a major cause of life-threatening complications in patients receiving anticancer chemotherapy. The spectrum and susceptibility profiles of causative microorganisms differ with time and place. Data from Lebanon are scarce. We aim at evaluating the epidemiology of bacteremia in cancer patients in a university hospital in Lebanon, emphasizing antibiotic resistance and risk factors of multi-drug resistant organism (MDRO-associated bacteremia.This is a retrospective study of 75 episodes of bacteremia occurring in febrile neutropenic patients admitted to the hematology-oncology unit at Makassed General Hospital, Lebanon, from October 2009-January 2012.It corresponds to epidemiological data on bacteremia episodes in febrile neutropenic cancer patients including antimicrobial resistance and identification of risk factors associated with third generation cephalosporin resistance (3GCR and MDRO-associated bacteremia. Out of 75 bacteremias, 42.7% were gram-positive (GP, and 57.3% were gram-negative (GN. GP bacteremias were mostly due to methicillin-resistant coagulase negative staphylococci (28% of total bacteremias and 66% of GP bacteremias. Among the GN bacteremias, Escherichia coli (22.7% of total, 39.5% of GN organisms and Klebsiellapneumoniae(13.3% of total, 23.3% of GN organisms were the most important causative agents. GN bacteremia due to 3GC sensitive (3GCS bacteria represented 28% of total bacteremias, while 29% were due to 3GCR bacteria and 9% were due to carbapenem-resistant organisms. There was a significant correlation between bacteremia with MDRO and subsequent intubation, sepsis and mortality. Among potential risk factors, only broad spectrum antibiotic intake >4 days before bacteremia was found to be statistically significant for acquisition of 3GCR bacteria. Using carbapenems or piperacillin/ tazobactam>4 days before bacteremia was significantly associated with the emergence of MDRO (p value<0.05.

  3. Novel Clostridium difficile Anti-Toxin (TcdA and TcdB Humanized Monoclonal Antibodies Demonstrate In Vitro Neutralization across a Broad Spectrum of Clinical Strains and In Vivo Potency in a Hamster Spore Challenge Model.

    Directory of Open Access Journals (Sweden)

    Hongyu Qiu

    Full Text Available Clostridium difficile (C. difficile infection (CDI is the main cause of nosocomial antibiotic-associated colitis and increased incidence of community-associated diarrhea in industrialized countries. At present, the primary treatment of CDI is antibiotic administration, which is effective but often associated with recurrence, especially in the elderly. Pathogenic strains produce enterotoxin, toxin A (TcdA, and cytotoxin, toxin B (TcdB, which are necessary for C. difficile induced diarrhea and gut pathological changes. Administration of anti-toxin antibodies provides an alternative approach to treat CDI, and has shown promising results in preclinical and clinical studies. In the current study, several humanized anti-TcdA and anti-TcdB monoclonal antibodies were generated and their protective potency was characterized in a hamster infection model. The humanized anti-TcdA (CANmAbA4 and anti-TcdB (CANmAbB4 and CANmAbB1 antibodies showed broad spectrum in vitro neutralization of toxins from clinical strains and neutralization in a mouse toxin challenge model. Moreover, co-administration of humanized antibodies (CANmAbA4 and CANmAbB4 cocktail provided a high level of protection in a dose dependent manner (85% versus 57% survival at day 22 for 50 mg/kg and 20 mg/kg doses, respectively in a hamster gastrointestinal infection (GI model. This study describes the protective effects conferred by novel neutralizing anti-toxin monoclonal antibodies against C. difficile toxins and their potential as therapeutic agents in treating CDI.

  4. 贵州铜仁产广谱抑菌作用细菌素乳酸菌的筛选及鉴定%On the Sift and Identification of the Broad-spectrum Antibacterial Bacteriocin Produced in Tongren, Guizhou

    Institute of Scientific and Technical Information of China (English)

    胡美忠; 张新卓; 刘芸

    2014-01-01

    从贵州铜仁产发酵食品中分离纯化出70余株乳酸菌,采用Agar-spot-test初筛与排除酸、过氧化氢抑制后复筛出一株能产广谱抑菌作用细菌素的乳酸菌(编号G55),经生理生化及16S rDNA鉴定可知G55为植物乳杆菌。抑菌谱实验表明,G55产生的细菌素能抑制革兰阳性菌及革兰阴性菌的生长;蛋白酶实验表明,G55产生的细菌素对胃蛋白酶、蛋白酶K敏感,对胰蛋白酶、α凝乳蛋白酶部分敏感。%More than 70 strains of lactic acid bacteria are separated and purified from the fermented foods made in Tongren, Guizhou. First, they are preliminarily sifted by means of agar-spot-test and then excluded from the inhibition of the acid and hydrogen peroxide. After a second sift, a strain of lactic acid bacteria named G55 which can produce broad-spectrum antibacterial bacteriocin is chosen from them. After the physiobiochemical experiment and the 16SrDNA identification, it is concluded that G55 is an actobacillus plantarum. According to the antibacterial spectrum experiment, it shows that the bacteriocin produced by G55 can inhibit the growth of both gram-positive bacteria and gram-negative bacteria. Meanwhile, the experiment of protease shows that the bacteriorin is sensitive to pepsin and proteinase K and is partially sensitive to trypsin andαcurd protease.

  5. Novel approaches to antifungal prophylaxis.

    Science.gov (United States)

    Ostrosky-Zeichner, Luis

    2004-06-01

    Antifungal prophylaxis represents a significant advance in the management of patients at risk from fungal infections in a variety of settings. Identification of patients at the highest risk and the utilisation of safe and effective drugs maximises the benefits of prophylaxis. Situations in which antifungal prophylaxis has been shown to be useful are bone marrow transplantation, liver and lung transplantation, surgical and neonatal intensive care units, secondary prophylaxis of fungal infections associated with HIV and neutropenia associated haematological malignancies and their treatment. New antifungal agents, such as the echinocandins and the new azoles, are available and have a potential role in antifungal prophylaxis. Future studies should evaluate which strategy is more useful; prophylaxis or pre-emptive therapy.

  6. AN OVERVIEW ON ANTIFUNGAL THERAPY

    OpenAIRE

    Karki, Nirmal K.; Ahmed, Azhar; Charde, Rita; Charde, Manoj; Gandhare, Bhushan

    2011-01-01

    The number of fungi causing systemic disease is growing and the number of systemic diseases caused by fungi is increasing. The currently available antifungal agents for the treatment of systemic mycoses include polyene antibiotics (Amphotericin B), fluoropyrimidine (Flu cytosine), and Nystatin andazole group of drugs (Ketoconazole, Fluconazole, and Itraconazole). Novel drug delivery systems for antifungal therapy, based on the type of formulation are classified as Liposomes Nanocochleates, Na...

  7. 2-(Substituted phenyl-3,4-dihydroisoquinolin-2-iums as Novel Antifungal Lead Compounds: Biological Evaluation and Structure-Activity Relationships

    Directory of Open Access Journals (Sweden)

    Xin-Juan Yang

    2013-08-01

    Full Text Available The title compounds are a class of structurally simple analogues of quaternary benzo[c]phenanthridine alkaloids (QBAs. In order to develop novel QBA-like antifungal drugs, in this study, 24 of the title compounds with various substituents on the N-phenyl ring were evaluated for bioactivity against seven phytopathogenic fungi using the mycelial growth rate method and their SAR discussed. Almost all the compounds showed definite activities in vitro against each of the test fungi at 50 μg/mL and a broad antifungal spectrum. In most cases, the mono-halogenated compounds 2–12 exhibited excellent activities superior to the QBAs sanguinarine and chelerythrine. Compound 8 possessed the strongest activities on each of the fungi with EC50 values of 8.88–19.88 µg/mL and a significant concentration-dependent relationship. The SAR is as follows: the N-phenyl group is a high sensitive structural moiety for the activity and the characteristics and position of substituents intensively influence the activity. Generally, electron-withdrawing substituents remarkably enhance the activity while electron-donating substituents cause a decrease of the activity. In most cases, ortha- and para-halogenated isomers were more active than the corresponding m-halogenated isomers. Thus, the title compounds emerged as promising lead compounds for the development of novel biomimetic antifungal agrochemicals. Compounds 8 and 2 should have great potential as new broad spectrum antifungal agents for plant protection.

  8. Third generation cephalosporin resistant Enterobacteriaceae and multidrug resistant gram-negative bacteria causing bacteremia in febrile neutropenia adult cancer patients in Lebanon, broad spectrum antibiotics use as a major risk factor, and correlation with poor prognosis.

    Science.gov (United States)

    Moghnieh, Rima; Estaitieh, Nour; Mugharbil, Anas; Jisr, Tamima; Abdallah, Dania I; Ziade, Fouad; Sinno, Loubna; Ibrahim, Ahmad

    2015-01-01

    Bacteremia remains a major cause of life-threatening complications in patients receiving anticancer chemotherapy. The spectrum and susceptibility profiles of causative microorganisms differ with time and place. Data from Lebanon are scarce. We aim at evaluating the epidemiology of bacteremia in cancer patients in a university hospital in Lebanon, emphasizing antibiotic resistance and risk factors of multi-drug resistant organism (MDRO)-associated bacteremia. This is a retrospective study of 75 episodes of bacteremia occurring in febrile neutropenic patients admitted to the hematology-oncology unit at Makassed General Hospital, Lebanon, from October 2009-January 2012. It corresponds to epidemiological data on bacteremia episodes in febrile neutropenic cancer patients including antimicrobial resistance and identification of risk factors associated with third generation cephalosporin resistance (3GCR) and MDRO-associated bacteremia. Out of 75 bacteremias, 42.7% were gram-positive (GP), and 57.3% were gram-negative (GN). GP bacteremias were mostly due to methicillin-resistant coagulase negative staphylococci (28% of total bacteremias and 66% of GP bacteremias). Among the GN bacteremias, Escherichia coli (22.7% of total, 39.5% of GN organisms) and Klebsiella pneumoniae(13.3% of total, 23.3% of GN organisms) were the most important causative agents. GN bacteremia due to 3GC sensitive (3GCS) bacteria represented 28% of total bacteremias, while 29% were due to 3GCR bacteria and 9% were due to carbapenem-resistant organisms. There was a significant correlation between bacteremia with MDRO and subsequent intubation, sepsis and mortality. Among potential risk factors, only broad spectrum antibiotic intake >4 days before bacteremia was found to be statistically significant for acquisition of 3GCR bacteria. Using carbapenems or piperacillin/tazobactam>4 days before bacteremia was significantly associated with the emergence of MDRO (p < 0.05). Our findings have major

  9. 葡萄球菌肠毒素超抗原广谱抑制性多肽的功能研究%Study on the function of a broad-spectrum inhibitory peptide against SEs superantigen

    Institute of Scientific and Technical Information of China (English)

    王思雄; 李亚斐; 马惠文; 邵江河; 余慧青; 王东林

    2012-01-01

    目的 在前期筛选出针对SEA、SEB、SEC具有广谱抑制性的多肽P72基础上,通过竞争结合实验和动物模型对多肽P72的抑制机制进行探讨.方法 采用竞争结合实验检测多肽P72与MHCⅡ类分子的亲合力;利用“两次攻击(two-hit)法”建立的动物模型研究P72对SEs的体内抑制活性.结果 P72不能与FITC-SEs有效竞争结合Raji细胞上的MHCⅡ类分子,P72对SEA、SEB和SEC致Balb/c小鼠休克效应具有显著的保护作用.结论 P72可能不是与MHCⅡ类分子结合而产生的抑制作用,P72能够在体内抑制SEs的超抗原活性,其具体的抑制机制有待深入研究.%This study aims lo investigate the mechanism of the broad-spectrum inhibitory activity of synthetic peptide P72 against SEA, SEB and SEC based on the previous research of competition assay and animal experiments. We detected the binding ability of the peptide P72 to MHC class Ⅱ molecules by competition assay and assessed the in vivo biological activity of peptide P72 against SEs by the "two-hit animal model. The results indicated that the peptide P72 could not bind to MHC class Ⅱ molecules, while P72 can completely protect most of the Balb/c mice against toxic shock induced by SEA, SEB and SEC. In conclusion, our study demonstrates that the inhibitory activity of peptide P72 may not due lo binding to MHC Ⅱ . And peptide P72 can inhibit the biological activity of SEs in vivo. But the exact mechanism of inhibitory activity of P72 still needs studies.

  10. Update on Antifungal Drug Resistance

    Science.gov (United States)

    Shor, Erika; Zhao, Yanan

    2015-01-01

    Invasive fungal infections remain a major source of global morbidity and mortality, especially among patients with underlying immune suppression. Successful patient management requires antifungal therapy. Yet, treatment choices are restricted due to limited classes of antifungal agents and the emergence of antifungal drug resistance. In some settings, the evolution of multidrug-resistant strains insensitive to several classes of antifungal agents is a major concern. The resistance mechanisms responsible for acquired resistance are well characterized and include changes in drug target affinity and abundance, and reduction in the intracellular level of drug by biofilms and efflux pumps. The development of high-level and multidrug resistance occurs through a stepwise evolution of diverse mechanisms. The genetic factors that influence these mechanisms are emerging and they form a complex symphony of cellular interactions that enable the cell to adapt and/or overcome drug-induced stress. Drivers of resistance involve a complex blend of host and microbial factors. Understanding these mechanisms will facilitate development of better diagnostics and therapeutic strategies to overcome and prevent antifungal resistance. PMID:26120512

  11. Penetratin and derivatives acting as antifungal agents

    NARCIS (Netherlands)

    Masman, Marcelo F.; Rodriguez, Ana M.; Raimondi, Marcela; Zacchino, Susana A.; Luiten, Paul G. M.; Somlai, Csaba; Kortvelyesi, Tamas; Penke, Botond; Enriz, Ricardo D.

    2009-01-01

    The synthesis, in vitro evaluation, and conformational study of RQIKTWFQNRRMKWKK-NH(2) (penetratin) and related derivatives acting as antifungal agents are reported. Penetratin and some of its derivatives displayed antifungal activity against the human opportunistic pathogenic standardized ATCC stra

  12. Size-resolved characterization of the polysaccharidic and proteinaceous components of sea spray aerosol

    Science.gov (United States)

    Aller, Josephine Y.; Radway, JoAnn C.; Kilthau, Wendy P.; Bothe, Dylan W.; Wilson, Theodore W.; Vaillancourt, Robert D.; Quinn, Patricia K.; Coffman, Derek J.; Murray, Benjamin J.; Knopf, Daniel A.

    2017-04-01

    Dissolved organic polymers released by phytoplankton and bacteria abiologically self-assemble in surface ocean waters into nano-to micro-sized gels containing polysaccharides, proteins, lipids and other components. These gels concentrate in the sea surface microlayer (SML), where they can potentially contribute to sea spray aerosol (SSA). Sea spray is a major source of atmospheric aerosol mass over much of the earth's surface, and knowledge of its properties (including the amount and nature of the organic content), size distributions and fluxes are fundamental for determining its role in atmospheric chemistry and climate. Using a cascade impactor, we collected size-fractionated aerosol particles from ambient air and from freshly generated Sea Sweep SSA in the western North Atlantic Ocean together with biological and chemical characterization of subsurface and SML waters. Spectrophotometric methods were applied to quantify the polysaccharide-containing transparent exopolymer (TEP) and protein-containing Coomassie stainable material (CSM) in these particles and waters. This study demonstrates that both TEP and CSM in surface ocean waters are aerosolized with sea spray with the greatest total TEP associated with particles 5 000 nm. The higher concentrations of TEP and CSM in particles >5 000 nm most likely reflects collection of microorganism cells and/or fragments. The greater concentration of CSM in larger size particles may also reflect greater stability of proteinaceous gels compared to polysaccharide-rich gels in surface waters and the SML. Both TEP and CSM were measured in the ambient marine air sample with concentrations of 2.1 ± 0.16 μg xanthan gum equivalents (XG eq.) m-3 and 14 ± 1.0 μg bovine serum albumin equivalents (BSA eq.) m-3. TEP in Sea Sweep SSA averaged 4.7 ± 3.1 μg XG eq. m-3 and CSM 8.6 ± 7.3 μg BSA eq. m-3. This work shows the transport of marine biogenic material across the air-sea interface through primary particle emission and the

  13. Special Issue: Novel Antifungal Drug Discovery

    Directory of Open Access Journals (Sweden)

    Maurizio Del Poeta

    2016-12-01

    Full Text Available This Special Issue is designed to highlight the latest research and development on new antifungal compounds with mechanisms of action different from the ones of polyenes, azoles, and echinocandins. The papers presented here highlight new pathways and targets that could be exploited for the future development of new antifungal agents to be used alone or in combination with existing antifungals. A computational model for better predicting antifungal drug resistance is also presented.

  14. Treating chromoblastomycosis with systemic antifungals.

    Science.gov (United States)

    Bonifaz, Alexandro; Paredes-Solís, Vanessa; Saúl, Amado

    2004-02-01

    Chromoblastomycosis is a subcutaneous mycosis for which there is no treatment of choice but rather, several treatment options, with low cure rates and many relapses. The choice of treatment should consider several conditions, such as the causal agent (the most common one being Fonsecaea pedrosoi ), extension of the lesions, clinical topography and health status of the patient. Most oral and systemic antifungals have been used; the best results have been obtained with itraconazole and terbinafine at high doses, for a mean of 6 - 12 months. In extensive and refractory cases, chemotherapy with oral antifungals may be associated with thermotherapy (local heat and/or cryosurgery). Limited or early cases may be managed with surgical methods, always associated with oral antifungal agents. It is important to determine the in vitro sensitivity of the major causal agents to the various drugs, by estimating the minimum inhibitory concentration, as well as drug tolerability and drug interactions.

  15. ANTIFUNGAL PROPHYLAXIS IN IMMUNOCOMPROMISED PATIENTS

    Directory of Open Access Journals (Sweden)

    Lourdes Vazquez

    2016-09-01

    Full Text Available Invasive fungal infections (IFIs represent significant complications in patients with hematological malignancies. Chemoprevention of IFIs may be important in this setting, but most antifungal drugs have demonstrated poor efficacy, particularly in the prevention of invasive aspergillosis. Antifungal prophylaxis in hematological patients is currently regarded as the gold standard in situations with a high risk of infection, such as acute leukemia, myelodysplastic syndromes, and autologous or allogeneic hematopoietic stem cell transplantation. Over the years, various scientific societies have established a series of recommendations for antifungal prophylaxis based on prospective studies performed with different drugs. However, the prescription of each agent must be personalized, adapting its administration to the characteristics of individual patients and taking into account possible interactions with concomitant medication.

  16. In vitro antifungal activity of silver nanoparticles against ocular pathogenic filamentous fungi.

    Science.gov (United States)

    Xu, Yan; Gao, Chuanwen; Li, Xiaohua; He, Yi; Zhou, Lutan; Pang, Guangren; Sun, Shengtao

    2013-03-01

    Fungal keratitis is emerging as a major cause of vision loss in a developing country such as China because of higher incidence and the unavailability of effective antifungals. It is urgent to explore broad-spectrum antifungals to effectively suppress ocular fungal pathogens, and to develop new antifungal eye drops to combat this vision-threatening infection. The aim of this study is to investigate the antifungal activity of silver nanoparticles (nano-Ag) in comparison with that of natamycin against ocular pathogenic filamentous fungi in vitro. Susceptibility tests were performed against 216 strains of fungi isolated from patients with fungal keratitis from the Henan Eye Institute in China by broth dilution antifungal susceptibility test of filamentous fungi approved by the Clinical and Laboratory Standards Institute M38-A document. The isolates included 112 Fusarium isolates (82 Fusarium solani species complex, 20 Fusarium verticillioides species complex, and 10 Fusarium oxysporum species complex), 94 Aspergillus isolates (61 Aspergillus flavus species complex, 11 Aspergillus fumigatus species complex, 12 Aspergillus versicolor species complex, and 10 Aspergillus niger species complex), and 10 Alternaria alternata isolates. The minimum inhibitory concentration (MIC) range and mode, the MIC for 50% of the strains tested (MIC50 value), and the MIC90 value were provided for the isolates with the SPSS statistical package. MIC50 value of nano-Ag were 1, 0.5, and 0.5 μg/mL for Fusarium spp., Aspergillus spp., and Al. alternata, respectively. MIC90 values of nano-Ag were 1, 1, and 1 μg/mL for Fusarium spp., Aspergillus spp., and Al. alternata, respectively. MIC50 values of natamycin were 4, 32, and 4 μg/mL for Fusarium spp., Aspergillus spp., and Al. alternata, respectively. MIC90 values of natamycin were 8, 32, and 4 μg/mL for Fusarium spp., Aspergillus spp., and Al. alternata, respectively. Nano-Ag, relative to natamycin, exhibits potent in vitro activity against

  17. Identification of a proteinaceous component in the leaf of moringa oleifera lam. with effects on high serum creatinine

    Directory of Open Access Journals (Sweden)

    S Sahoo

    2014-01-01

    Full Text Available Moringa oleifera Lam. has been an important plant in the history of mankind, both for its nutritional and medicinal uses. Apart from bactericidal effects, the parts of this plant have been effectively used in the treatment of circulatory, respiratory, endocrine, digestive as well as neural disorders. Till date, though, there has been no reported activity of the involvement of any proteinaceous extract from M. oleifera on high levels of serum creatinine. To address this issue, blood samples with high levels of serum creatinine (2 mg/dl and above were treated with leaf extract from M. oleifera. The crude extract was partially purified initially and eventually purified to completion as well. All these proteinaceous fractions were used to treat samples with high levels of serum creatinine as mentioned above. While the treatment of serum sample having high creatinine with crude extract and partially purified protein fractions showed a decrease of approximately 20% in the levels of serum creatinine over a period of 24 h, the samples treated with purified protein fraction reduced the serum creatinine level by 50%. In light of the fact that increased level of serum creatinine levels have adverse downstream effects on the heart, lungs and other organs, this communication assumes significance because it suggests a way of reducing the level of serum creatinine as an emergency measure. Further, the identification and characterisation of this proteinaceous component and possible in vivo experiments would provide a major tool for the treatment of downstream complications associated with increased serum creatinine via a new sources, albeit a natural one.

  18. Identification of a Proteinaceous Component in the Leaf of Moringa Oleifera lam. with Effects on High Serum Creatinine.

    Science.gov (United States)

    Sahoo, S; Raghavendra, K M; Biswas, S

    2014-01-01

    Moringa oleifera Lam. has been an important plant in the history of mankind, both for its nutritional and medicinal uses. Apart from bactericidal effects, the parts of this plant have been effectively used in the treatment of circulatory, respiratory, endocrine, digestive as well as neural disorders. Till date, though, there has been no reported activity of the involvement of any proteinaceous extract from M. oleifera on high levels of serum creatinine. To address this issue, blood samples with high levels of serum creatinine (2 mg/dl and above) were treated with leaf extract from M. oleifera. The crude extract was partially purified initially and eventually purified to completion as well. All these proteinaceous fractions were used to treat samples with high levels of serum creatinine as mentioned above. While the treatment of serum sample having high creatinine with crude extract and partially purified protein fractions showed a decrease of approximately 20% in the levels of serum creatinine over a period of 24 h, the samples treated with purified protein fraction reduced the serum creatinine level by 50%. In light of the fact that increased level of serum creatinine levels have adverse downstream effects on the heart, lungs and other organs, this communication assumes significance because it suggests a way of reducing the level of serum creatinine as an emergency measure. Further, the identification and characterisation of this proteinaceous component and possible in vivo experiments would provide a major tool for the treatment of downstream complications associated with increased serum creatinine via a new sources, albeit a natural one.

  19. Miconazole-loaded solid lipid nanoparticles: formulation and evaluation of a novel formula with high bioavailability and antifungal activity

    Directory of Open Access Journals (Sweden)

    Aljaeid BM

    2016-01-01

    Full Text Available Bader Mubarak Aljaeid,1 Khaled Mohamed Hosny1,2 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni Suef University, Beni Suef, Egypt Background and objective: Miconazole is a broad-spectrum antifungal drug that has poor aqueous solubility (<1 µg/mL; as a result, a reduction in its therapeutic efficacy has been reported. The aim of this study was to formulate and evaluate miconazole-loaded solid lipid nanoparticles (MN-SLNs for oral administration to find an innovative way to alleviate the disadvantages associated with commercially available capsules. Methods: MN-SLNs were prepared by hot homogenization/ultrasonication. The solubility of miconazole in different solid lipids was measured. The effect of process variables, such as surfactant types, homogenization and ultrasonication times, and the charge-inducing agent on the particle size, zeta potential, and encapsulation efficiency were determined. Furthermore, in vitro drug release, antifungal activity against Candida albicans, and in vivo pharmacokinetics were studied in rabbits. Results: The MN-SLN, consisting of 1.5% miconazole, 2% Precirol ATO5, 2.5% Cremophor RH40, 0.5% Lecinol, and 0.1% Dicetylphosphate, had an average diameter of 23 nm with a 90.2% entrapment efficiency. Furthermore, the formulation of MN-SLNs enhanced the antifungal activity compared with miconazole capsules. An in vivo pharmacokinetic study revealed that the bioavailability was enhanced by >2.5-fold. Conclusion: MN-SLN was more efficient in the treatment of candidiasis with enhanced oral bioavailability and could be a promising carrier for the oral delivery of miconazole. Keywords: miconazole, Precirol ATO5, solid lipid nanoparticles, encapsulation, Cremophor RH40, antifungal activity

  20. Biochemical approaches to selective antifungal activity. Focus on azole antifungals.

    Science.gov (United States)

    Vanden Bossche, H; Marichal, P; Gorrens, J; Coene, M C; Willemsens, G; Bellens, D; Roels, I; Moereels, H; Janssen, P A

    1989-01-01

    Azole antifungals (e.g. the imidazoles: miconazole, clotrimazole, bifonazole, imazalil, ketoconazole, and the triazoles: diniconazole, triadimenol, propiconazole, fluconazole and itraconazole) inhibit in fungal cells the 14 alpha-demethylation of lanosterol or 24-methylenedihydrolanosterol. The consequent inhibition of ergosterol synthesis originates from binding of the unsubstituted nitrogen (N-3 or N-4) of their imidazole or triazole moiety to the heme iron and from binding of their N-1 substituent to the apoprotein of a cytochrome P-450 (P-450(14)DM) of the endoplasmic reticulum. Great differences in both potency and selectivity are found between the different azole antifungals. For example, after 16h of growth of Candida albicans in medium supplemented with [14C]-acetate and increasing concentrations of itraconazole, 100% inhibition of ergosterol synthesis is achieved at 3 x 10(-8) M. Complete inhibition of this synthesis by fluconazole is obtained at 10(-5) M only. The agrochemical imidazole derivative, imazalil, shows high selectivity, it has almost 80 and 98 times more affinity for the Candida P-450(s) than for those of the piglet testes microsomes and bovine adrenal mitochondria, respectively. However, the topically active imidazole antifungal, bifonazole, has the highest affinity for P-450(s) of the testicular microsomes. The triazole antifungal itraconazole inhibits at 10(-5) M the P-450-dependent aromatase by 17.9, whereas 50% inhibition of this enzyme is obtained at about 7.5 x 10(-6)M of the bistriazole derivative fluconazole. The overall results show that both the affinity for the fungal P-450(14)DM and the selectivity are determined by the nitrogen heterocycle and the hydrophobic N-1 substituent of the azole antifungals. The latter has certainly a greater impact. The presence of a triazole and a long hypdrophobic nonligating portion form the basis for itraconazole's potency and selectivity.

  1. Antifungal constituents of Melicope borbonica

    DEFF Research Database (Denmark)

    Simonsen, Henrik Toft; Adsersen, Anne; Bremner, Paul

    2004-01-01

    , as the major constituents. All three compounds exhibited moderate antifungal activity against Candida albicans and Penicillium expansum, in accordance with the traditional use of the plant. Moreover, 2,4,6-trimethoxyacetophenone (methylxanthoxylin), three other coumarins [7-(3-methyl-2-butenyloxy)-6...

  2. Antifungal resistance in yeast vaginitis.

    Science.gov (United States)

    Dun, E.

    1999-01-01

    The increased number of vaginal yeast infections in the past few years has been a disturbing trend, and the scientific community has been searching for its etiology. Several theories have been put forth to explain the apparent increase. First, the recent widespread availability of low-dosage, azole-based over-the-counter antifungal medications for vaginal yeast infections encourages women to self-diagnose and treat, and women may be misdiagnosing themselves. Their vaginitis may be caused by bacteria, parasites or may be a symptom of another underlying health condition. As a result, they may be unnecessarily and chronically expose themselves to antifungal medications and encourage fungal resistance. Second, medical technology has increased the life span of seriously immune compromised individuals, yet these individuals are frequently plagued by opportunistic fungal infections. Long-term and intense azole-based antifungal treatment has been linked to an increase in resistant Candida and non-Candida species. Thus, the future of limiting antifungal resistance lies in identifying the factors promoting resistance and implementing policies to prevent it. PMID:10907778

  3. Expression dynamics of secreted protease genes in Trichophyton rubrum induced by key host's proteinaceous components.

    Science.gov (United States)

    Leng, Wenchuan; Liu, Tao; Wang, Jin; Li, Ruoyu; Jin, Qi

    2009-11-01

    Trichophyton rubrum is the most common agent of dermatophytosis, a disease that affects millions of individuals worldwide. Its molecular pathogenicity mechanisms are still not completely elucidated. It has been widely recognized that proteases secreted by T. rubrum are the key virulence factors during host infection. However, our knowledge about the expression of its secreted proteases in host infection is still obscure. This investigation provides the expression patterns and dynamics of secreted protease genes belonging to the subtilisins (SUB) and metalloproteases (MEP) gene families in T. rubrum. The data was obtained under simulated host infection conditions through relative quantification of real time PCR. Keratin, collagen, and elastin induced the expression of similar protease genes, and the expression patterns and dynamics of these protease genes in media containing human skin sections were different from those in media containing individual protein substrates. According to the expression dynamics of these protease genes, we conclude that Sub3, Sub4, and Mep4 may be the dominant proteases secreted by T. rubrum during host infection, and that these proteases could be good targets for new antifungal chemotherapy and molecular diagnostic markers. This work presents useful molecular details to further our understanding of the pathogenesis of dermatophytosis.

  4. Naturally occurring proteinaceous nanoparticles in Coptidis Rhizoma extract act as concentration-dependent carriers that facilitate berberine absorption.

    Science.gov (United States)

    Ma, Bing-Liang; Yin, Chun; Zhang, Bo-Kai; Dai, Yan; Jia, Yi-Qun; Yang, Yan; Li, Qiao; Shi, Rong; Wang, Tian-Ming; Wu, Jia-Sheng; Li, Yuan-Yuan; Lin, Ge; Ma, Yue-Ming

    2016-01-29

    Pharmacological activities of some natural products diminish and even disappear after purification. In this study, we explored the mechanisms underlying the decrease of acute oral toxicity of Coptidis Rhizoma extract after purification. The water solubility, in vitro absorption, and plasma exposure of berberine (the major active compound) in the Coptidis Rhizoma extract were much better than those of pure berberine. Scanning electron microscopy, laser scanning confocal microscopy (LSCM), and dynamic light scattering experiments confirmed that nanoparticles attached to very fine precipitates existed in the aqueous extract solution. The LSCM experiment showed that the precipitates were absorbed with the particles by the mouse intestine. High-speed centrifugation of the extract could not remove the nanoparticles and did not influence plasma exposure or acute oral toxicity. However, after extract dilution, the attached precipitates vanished, although the nanoparticles were preserved, and there were no differences in the acute oral toxicity and plasma exposure between the extract and pure berberine. The nanoparticles were then purified and identified as proteinaceous. Furthermore, they could absorb co-dissolved berberine. Our results indicate that naturally occurring proteinaceous nanoparticles in Coptidis Rhizoma extract act as concentration-dependent carriers that facilitate berberine absorption. These findings should inspire related studies in other natural products.

  5. Novel control methods for insect pests: development of a microencapsulation procedure for proteinaceous bioactives intended for oral delivery.

    Science.gov (United States)

    Richards, Elaine H; Wontner-Smith, Tim; Bradish, Hannah; Dani, M Paulina; Cotterill, Jane V

    2015-09-01

    The objective was to develop an environmentally favourable microcapsule suitable for delivery of proteinaceous bioactive agents ('bioinsecticides') to pest insects. Utilising feeding bioassays, we determined that microspheres made of alginate can be produced in a variety of sizes and are palatable and non-toxic to larvae of the lepidopteran pest Lacanobia oleracea. Dehydrated microspheres were also readily ingested by larvae. Using a novel feeding bioassay and alginate microspheres containing a fluorescent marker material (coumarin 7 encapsulated in styrene maleic anhydride beads), we determined that the microspheres successfully deliver the marker to the insect gut. Moreover, the alginate microspheres rapidly break down in the alkaline conditions of the insect gut and release their contents, the beads passing through the gut in 2-3 h. Using bovine serum albumin as a test protein and western blotting, it was determined that alginate can successfully encapsulate protein, and that the microspheres can be stored in a CaCl2 solution for up to 24 days without extensive leakage. Importantly, it was also determined that alginate and the microsphere-making procedure developed do not inactivate rVPr1 (an insect immunosuppressive protein and potential bioinsecticide). An alginate-based microsphere has potential to deliver the proteinaceous bioactive rVPr1 to pest insects. © 2014 Crown copyright. Pest Management Science © 2014 Society of Chemical Industry.

  6. Lack of effect of cell-wall targeted antibacterials on biofilm formation and antifungal susceptibility of Candidaspecies

    Directory of Open Access Journals (Sweden)

    Gisela Myrian de Lima Leite

    2014-09-01

    Full Text Available The use of central venous catheters (CVC and broad-spectrum antibacterials are among the main risk factors for the development of candidemia in patients admitted to intensive care units (ICU. It is known that some antibacterials increase the resistance of these yeasts to azole antifungals. Thus, the aim of this research was to determine whether yeast present in CVC colonizations previously exposed to cell-wall targeted antibacterials benefit from a reduction in susceptibility to fluconazole and voriconazole, facilitating their ability to form biofilms. Candida albicans, C. tropicalis, C. glabrata, C. parapsilosis and C. guilhermondii were seeded into antibacterial (cefepime, meropenem, vancomycin, and piperacillin-tazobactam gradient plates produced in Mueller-Hinton Agar. The susceptibility to fluconazole and voriconazole and the biofilm formation of the yeasts were tested before and after exposure to the antibacterials. None of the antibacterials exerted a significant effect on the in vitro susceptibility of the yeasts to the antifungal agents or on their ability to form biofilms. These results suggest that increased candidemia in ICU patients is not attributable to possible alterations in the yeasts, but is more likely caused by a weakening of the patient's general condition after long exposure to infection.

  7. Natural products as sources of new fungicides (III): Antifungal activity of 2,4-dihydroxy-5-methylacetophenone derivatives.

    Science.gov (United States)

    Shi, Wei; Dan, Wen-Jia; Tang, Jiang-Jiang; Zhang, Yan; Nandinsuren, Tseden; Zhang, An-Ling; Gao, Jin-Ming

    2016-05-01

    A series of new 2,4-dihydroxy-5-methylacetophenone 2 derivatives were synthesized, and characterized by (1)H, (13)C NMR and ESI-MS. Their antifungal activities were evaluated in vitro against five important plant fungal pathogens including Cytospora sp., Glomerella cingulate, Pyricularia oryzaecar, Botrytis cinerea and Alternaria solani by the mycelial growth inhibitory rate assay. Compounds 2b-d, 2g and 2h displayed a broad-spectrum activity. The logP value of these active compounds is ranging from 1.71 to 2.54. Especially, isopropyl ketone 2g (logP 2.27) was found to be the most active to the tested organisms with IC50 values of 17.28-32.32 μg/mL. The results suggest that compound 2g might be a promising candidate in the development of new agrochemical antifungal agents. Preliminary structure-activity relationship (SAR) studies of the acetophenone derivatives are also discussed.

  8. Amphotericin B-copper(II) complex as a potential agent with higher antifungal activity against Candida albicans.

    Science.gov (United States)

    Chudzik, Barbara; Tracz, Izabela B; Czernel, Grzegorz; Fiołka, Marta J; Borsuk, Grzegorz; Gagoś, Mariusz

    2013-08-16

    Amphotericin B (AmB) is a polyene antibiotic produced by Streptomyces nodosus used for more than 50 years in the treatment of acute systemic fungal infections. It exhibits a broad spectrum of activity against fungal and protozoan pathogens with relatively rare resistance. The aim of this study was to prepare and evaluate the utility of the AmB-Cu(2+) complex as a potential compound with a high fungicidal activity at lower concentrations, compared with conventional AmB. It was hypothesized that insertion of copper ions into fungal cell membranes, together with the AmB-Cu(2+) complex bypassing the natural homeostatic mechanisms of this element, may contribute to the increased fungicidal activity of AmB. The analysis of results indicates the increased antifungal activity of the AmB-Cu(2+) complex against Candida albicans in comparison with the pure AmB and Fungizone. Additionally, it was stated that the increased antifungal activity of the AmB-Cu(2+) complex is not the sum of the toxic effects of AmB and Cu(2+) ions, but is a result of the unique structure of this compound.

  9. New insights into the structure and mode of action of Mo-CBP3, an antifungal chitin-binding protein of Moringa oleifera seeds.

    Directory of Open Access Journals (Sweden)

    Adelina B Batista

    Full Text Available Mo-CBP3 is a chitin-binding protein purified from Moringa oleifera Lam. seeds that displays inhibitory activity against phytopathogenic fungi. This study investigated the structural properties and the antifungal mode of action of this protein. To this end, circular dichroism spectroscopy, antifungal assays, measurements of the production of reactive oxygen species and microscopic analyses were utilized. Mo-CBP3 is composed of 30.3% α-helices, 16.3% β-sheets, 22.3% turns and 30.4% unordered forms. The Mo-CBP3 structure is highly stable and retains its antifungal activity regardless of temperature and pH. Fusarium solani was used as a model organism for studying the mechanisms by which this protein acts as an antifungal agent. Mo-CBP3 significantly inhibited spore germination and mycelial growth at 0.05 mg.mL-1. Mo-CBP3 has both fungistatic and fungicidal effects, depending on the concentration used. Binding of Mo-CBP3 to the fungal cell surface is achieved, at least in part, via electrostatic interactions, as salt was able to reduce its inhibitory effect. Mo-CBP3 induced the production of ROS and caused disorganization of both the cytoplasm and the plasma membrane in F. solani cells. Based on its high stability and specific toxicity, with broad-spectrum efficacy against important phytopathogenic fungi at low inhibitory concentrations but not to human cells, Mo-CBP3 has great potential for the development of new antifungal drugs or transgenic crops with enhanced resistance to phytopathogens.

  10. New insights into the structure and mode of action of Mo-CBP3, an antifungal chitin-binding protein of Moringa oleifera seeds.

    Science.gov (United States)

    Batista, Adelina B; Oliveira, José T A; Gifoni, Juliana M; Pereira, Mirella L; Almeida, Marina G G; Gomes, Valdirene M; Da Cunha, Maura; Ribeiro, Suzanna F F; Dias, Germana B; Beltramini, Leila M; Lopes, José Luiz S; Grangeiro, Thalles B; Vasconcelos, Ilka M

    2014-01-01

    Mo-CBP3 is a chitin-binding protein purified from Moringa oleifera Lam. seeds that displays inhibitory activity against phytopathogenic fungi. This study investigated the structural properties and the antifungal mode of action of this protein. To this end, circular dichroism spectroscopy, antifungal assays, measurements of the production of reactive oxygen species and microscopic analyses were utilized. Mo-CBP3 is composed of 30.3% α-helices, 16.3% β-sheets, 22.3% turns and 30.4% unordered forms. The Mo-CBP3 structure is highly stable and retains its antifungal activity regardless of temperature and pH. Fusarium solani was used as a model organism for studying the mechanisms by which this protein acts as an antifungal agent. Mo-CBP3 significantly inhibited spore germination and mycelial growth at 0.05 mg.mL-1. Mo-CBP3 has both fungistatic and fungicidal effects, depending on the concentration used. Binding of Mo-CBP3 to the fungal cell surface is achieved, at least in part, via electrostatic interactions, as salt was able to reduce its inhibitory effect. Mo-CBP3 induced the production of ROS and caused disorganization of both the cytoplasm and the plasma membrane in F. solani cells. Based on its high stability and specific toxicity, with broad-spectrum efficacy against important phytopathogenic fungi at low inhibitory concentrations but not to human cells, Mo-CBP3 has great potential for the development of new antifungal drugs or transgenic crops with enhanced resistance to phytopathogens.

  11. Enhanced antifungal effects of amphotericin B-TPGS-b-(PCL-ran-PGA nanoparticles in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Tang X

    2014-11-01

    Full Text Available Xiaolong Tang,1,2,* He Zhu,3,* Ledong Sun,4,* Wei Hou,2 Shuyu Cai,1 Rongbo Zhang,1 Feng Liu5 1Stem Cell Engineering Research Center, School of Medicine, Anhui University of Science and Technology, Huainan, People’s Republic of China; 2State Key Laboratory of Virology, Life Sciences College, Wuhan University, Wuhan, Hubei, People’s Republic of China; 3Institute of Skin Damage and Repair, General Hospital of Beijing Military Command, Beijing, People’s Republic of China; 4Department of Dermatology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 5Department of Anesthesiology, Children’s Hospital, Chongqing Medical University; Key Laboratory of Child Development and Disorders of the Ministry of Education, Chongqing, People’s Republic of China *These authors contributed equally to this work Background: Amphotericin B (AMB is a polyene antibiotic with broad spectrum antifungal activity, but its clinical toxicities and poor solubility limit the wide application of AMB in clinical practice. Recently, new drug-loaded nanoparticles (NPs – diblock copolymer D-α-tocopheryl polyethylene glycol 1000 succinate-b-poly(ε-caprolactone-ran-glycolide (PLGA-TPGS – have received special attention for their reduced toxicity, and increased effectiveness of drug has also been reported. This study aimed to develop AMB-loaded PLGA-TPGS nanoparticles (AMB-NPs and evaluate their antifungal effects in vitro and in vivo.Methods: AMB-NPs were prepared with a modified nanoprecipitation method and then characterized in terms of physical characteristics, in vitro drug release, stability, drug-encapsulation efficiency, and toxicity. Finally, the antifungal activity of AMB-NPs was investigated in vitro and in vivo.Results: AMB-NPs were stable and spherical, with an average size of around 110 nm; the entrapment efficacy was closed to 85%, and their release exhibited a typically biphasic pattern. The actual

  12. Defensins: antifungal lessons from eukaryotes

    Directory of Open Access Journals (Sweden)

    Patrícia M. Silva

    2014-03-01

    Full Text Available Over the last years, antimicrobial peptides (AMPs have been the focus of intense research towards the finding of a viable alternative to current antifungal drugs. Defensins are one of the major families of AMPs and the most represented among all eukaryotic groups, providing an important first line of host defense against pathogenic microorganisms. Several of these cysteine-stabilized peptides present a relevant effect against fungi. Defensins are the AMPs with the broader distribution across all eukaryotic kingdoms, namely, Fungi, Plantæ and Animalia, and were recently shown to have an ancestor in a bacterial organism. As a part of the host defense, defensins act as an important vehicle of information between innate and adaptive immune system and have a role in immunomodulation. This multidimensionality represents a powerful host shield, hard for microorganisms to overcome using single approach resistance strategies. Pathogenic fungi resistance to conventional antimycotic drugs is becoming a major problem. Defensins, as other AMPs, have shown to be an effective alternative to the current antimycotic therapies, demonstrating potential as novel therapeutic agents or drug leads. In this review, we summarize the current knowledge on some eukaryotic defensins with antifungal action. An overview of the main targets in the fungal cell and the mechanism of action of these AMPs (namely, the selectivity for some fungal membrane components are presented. Additionally, recent works on antifungal defensins structure, activity and citotoxicity are also reviewed.

  13. Novel antifungal α-hairpinin peptide from Stellaria media seeds: structure, biosynthesis, gene structure and evolution.

    Science.gov (United States)

    Slavokhotova, Anna A; Rogozhin, Eugene A; Musolyamov, Alexander K; Andreev, Yaroslav A; Oparin, Peter B; Berkut, Antonina A; Vassilevski, Alexander A; Egorov, Tsezi A; Grishin, Eugene V; Odintsova, Tatyana I

    2014-01-01

    Plant defense against disease is a complex multistage system involving initial recognition of the invading pathogen, signal transduction and activation of specialized genes. An important role in pathogen deterrence belongs to so-called plant defense peptides, small polypeptide molecules that present antimicrobial properties. Using multidimensional liquid chromatography, we isolated a novel antifungal peptide named Sm-AMP-X (33 residues) from the common chickweed (Stellaria media) seeds. The peptide sequence shows no homology to any previously described proteins. The peculiar cysteine arrangement (C(1)X3C(2)XnC(3)X3C(4)), however, allocates Sm-AMP-X to the recently acknowledged α-hairpinin family of plant defense peptides that share the helix-loop-helix fold stabilized by two disulfide bridges C(1)-C(4) and C(2)-C(3). Sm-AMP-X exhibits high broad-spectrum activity against fungal phytopathogens. We further showed that the N- and C-terminal "tail" regions of the peptide are important for both its structure and activity. The truncated variants Sm-AMP-X1 with both disulfide bonds preserved and Sm-AMP-X2 with only the internal S-S-bond left were progressively less active against fungi and presented largely disordered structure as opposed to the predominantly helical conformation of the full-length antifungal peptide. cDNA and gene cloning revealed that Sm-AMP-X is processed from a unique multimodular precursor protein that contains as many as 12 tandem repeats of α-hairpinin-like peptides. Structure of the sm-amp-x gene and two related pseudogenes sm-amp-x-ψ1 and sm-amp-x-ψ2 allows tracing the evolutionary scenario that led to generation of such a sophisticated precursor protein. Sm-AMP-X is a new promising candidate for engineering disease resistance in plants.

  14. A novel cysteine-rich antifungal peptide ToAMP4 from Taraxacum officinale Wigg. flowers.

    Science.gov (United States)

    Astafieva, A A; Rogozhin, Eugene A; Andreev, Yaroslav A; Odintsova, T I; Kozlov, S A; Grishin, Eugene V; Egorov, Tsezi A

    2013-09-01

    A novel peptide named ToAMP4 was isolated from Taraxacum officinale Wigg. flowers by a combination of acetic acid extraction and different types of chromatography: affinity, size-exclusion, and RP-HPLC. The amino acid sequence of ToAMP4 was determined by automated Edman degradation. The peptide is basic, consists of 41 amino acids, and incorporates three disulphide bonds. Due to the unusual cysteine spacing pattern, ToAMP4 does not belong to any known plant AMP family, but classifies together with two other antimicrobial peptides ToAMP1 and ToAMP2 previously isolated from the dandelion flowers. To study the biological activity of ToAMP4, it was successfully produced in a prokaryotic expression system as a fusion protein with thioredoxin. The recombinant peptide was shown to be identical to the native ToAMP4 by chromatographic behavior, molecular mass, and N-terminal amino acid sequence. The peptide displays broad-spectrum antifungal activity against important phytopathogens. Two ToAMP4-mediated inhibition strategies depending on the fungus were demonstrated. The results obtained add to our knowledge on the structural and functional diversity of AMPs in plants. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  15. Proteinaceous inhibitors of carbohydrate-active enzymes in cereals - implication in agriculture, cereal-processing and nutrition

    DEFF Research Database (Denmark)

    Juge, Nathalie; Svensson, Birte

    2006-01-01

    Enzymes that degrade, modify, or create glycosidic bonds are involved in carbohydrate biosynthesis and remodelling. Microbial carbohydrate-active enzymes form the basis of current green technology in the food, feed, starch, paper and pulp industries and the revolution in genomics may offer long......-term gains on the quality and quantity of the raw materials. Proteinaceous inhibitors of carbohydrate-active enzymes (alpha-amylase, limit-dextrinase, polygalacturonase, pectin lyase, pectin methylesterase, invertase and xyloglucan endoglucanase) naturally occur in plants where they are involved in various...... roles from plant defence to metabolism. Xylanase inhibitors represent the latest addition to this growing family. In this review, we will focus on the inhibitors of carbohydrate-active enzymes present in cereals, mostly represented by et-amylase and xylanase inhibitors, and summarise the existing...

  16. Antibacterial and antifungal compounds from marine fungi.

    Science.gov (United States)

    Xu, Lijian; Meng, Wei; Cao, Cong; Wang, Jian; Shan, Wenjun; Wang, Qinggui

    2015-06-02

    This paper reviews 116 new compounds with antifungal or antibacterial activities as well as 169 other known antimicrobial compounds, with a specific focus on January 2010 through March 2015. Furthermore, the phylogeny of the fungi producing these antibacterial or antifungal compounds was analyzed. The new methods used to isolate marine fungi that possess antibacterial or antifungal activities as well as the relationship between structure and activity are shown in this review.

  17. Antibacterial and Antifungal Compounds from Marine Fungi

    OpenAIRE

    Lijian Xu; Wei Meng; Cong Cao; Jian Wang; Wenjun Shan; Qinggui Wang

    2015-01-01

    This paper reviews 116 new compounds with antifungal or antibacterial activities as well as 169 other known antimicrobial compounds, with a specific focus on January 2010 through March 2015. Furthermore, the phylogeny of the fungi producing these antibacterial or antifungal compounds was analyzed. The new methods used to isolate marine fungi that possess antibacterial or antifungal activities as well as the relationship between structure and activity are shown in this review.

  18. In vitro antifungal and cytotoxicity activities of selected Tanzanian ...

    African Journals Online (AJOL)

    In vitro antifungal and cytotoxicity activities of selected Tanzanian medicinal plants. ... the antifungal and cytotoxic activities of four medicinal plants from Tanzania, ... exhibited antifungal activity against test fungal strains with MIC range of 0.78 ...

  19. GC/MS analytical procedure for the characterization of glycerolipids, natural waxes, terpenoid resins, proteinaceous and polysaccharide materials in the same paint microsample avoiding interferences from inorganic media.

    Science.gov (United States)

    Lluveras, Anna; Bonaduce, Ilaria; Andreotti, Alessia; Colombini, Maria Perla

    2010-01-01

    An innovative GC/MS procedure for the characterization of organic materials in samples from works of art was developed. It is based on a multistep chemical pretreatment of the samples based on the ammonia extraction of proteins and polysaccharide materials, in order to separate them from lipid and resinous materials. The extraction is then followed by the separation and purification of proteinaceous and polysaccharide materials before hydrolysis, based on the use of monolithic sorbent tip technology with a C4 stationary phase. Lipids and resins are saponified/salified separately. Three fractions are generated and analyzed separately by GC/MS, thus enabling a quantitative analysis to be performed on aldoses and uronic acids, amino acids, mono- and dicarboxylic aliphatic acids, to determine polysaccharide, proteinaceous, and glycerolipid materials and molecular pattern recognition for the natural resin and wax components. With this analytical procedure, for the first time, glycerolipids, natural waxes, and proteinaceous, resinous, and polysaccharide materials can be simultaneously characterized in the same microsample from painted works of art. This new analytical approach prevents any analytical difficulties arising when the sample is divided into several different aliquots to be chemically processed separately, in order to characterize the various classes of organic materials. The procedure was successfully applied to samples from paintings from the Bamiyan Buddhas and a panel painting from the 15th century, highlighting the occurrence of glycerolipids, animal and plant resins, proteinaceous and polysaccharide materials.

  20. INVESTIGATION OF ANTIFUNGAL ACTIVITY OF QUINOLINIUM DERIVATIVES

    Directory of Open Access Journals (Sweden)

    G. A. Alexandrova

    2013-01-01

    Full Text Available Abstract. Antifungal activity (Candida albicans, Candida krusei of some substituted quinolinium derivatives has been investigated. It was established that the most perspective compound for detail investigation of antifungal activity by labeled biomarkers method was N-phenylbenzoquinaldinium tetrafluoroborate.

  1. Study of broad-spectrum antibiotics and antiseptics resistance genes in Acinetobacter baumannii strains isolated from burned patients%鲍曼不动杆菌烧伤分离株广谱抗生素及消毒剂耐药基因研究

    Institute of Scientific and Technical Information of China (English)

    程华莉; 潘宇红; 黄璇; 吕国忠; 朱婕; 糜祖煌; 张烽

    2011-01-01

    目的 研究鲍曼不动杆菌烧伤分离株对广谱抗生素的耐药性及所携带的广谱抗生素及消毒剂耐药基因.方法 测定20株分离自烧伤患者的鲍曼不动杆菌对四环素、米诺环素、氯霉素、利福平、复方磺胺甲噁唑5种广谱抗生素的敏感性,PCR检测catB、cmlA、arr-2/3、tetA、tetB、smr-2、emrE、dfrA1、dfrA5、dfrA7、dfrA12、dfrA17、dfrB5、qacE△l-sull和intI 共15种基因.结果 20株细菌对5种抗生素的敏感率分别为10%、100%、0、0和5%.tetB、qacE△l-sull和intl基因检出率均为95%(19/20),其余12种基因为阴性,且一株静脉导管分离株携带了上述3种基因.结论 本组鲍曼不动杆菌烧伤分离株对除米诺环素外的广谱抗生素耐药严重,并携带了四环素类和消毒剂耐药基因.应规范此类抗生素在养殖业中的使用,同时采取措施防止多重耐药菌株利用静脉导管在烧伤科传播.%Objective To investigate the broad-spectrum antibiotics resistance and broad-spectrum antibiotics and antiseptics resistance genes of Acinetobacter baumannii strains isolated from burned patients.Methods Susceptibilities to tetracycline, minocycline, chloramphenicol, rifampicin and trimethoprim-sulfamethoxazole were tested.Subsequently, catB, cmlA, arr-2/3, tetA, tetB, smr-2, emrE, dfrA1, dfrA5, dfr4 7, dfr412, dfrA17, dfrB5, qacE⊿l-sull and intI were detected by PCR.Results Susceptibilities to five broad-spectrum antibiotics were 10%, 100%, 0, 0 and 5% respectively.19/20(95%) isolates carried tetB, qacE⊿l-sull and intI genes while other 12 genes were not detected.Notably, an isolate colonising a central venous catheter carried all three genes mentioned above.Conclusions Acinetobacter baumannii strains isolated from burned patients we studied had serious resistances to broad-spectrum antibiotics except minocycline and carried tetracyclines and antiseptics resistance genes.Accordingly, broad-spectrum antibiotics should be

  2. Active packaging with antifungal activities.

    Science.gov (United States)

    Nguyen Van Long, N; Joly, Catherine; Dantigny, Philippe

    2016-03-01

    There have been many reviews concerned with antimicrobial food packaging, and with the use of antifungal compounds, but none provided an exhaustive picture of the applications of active packaging to control fungal spoilage. Very recently, many studies have been done in these fields, therefore it is timely to review this topic. This article examines the effects of essential oils, preservatives, natural products, chemical fungicides, nanoparticles coated to different films, and chitosan in vitro on the growth of moulds, but also in vivo on the mould free shelf-life of bread, cheese, and fresh fruits and vegetables. A short section is also dedicated to yeasts. All the applications are described from a microbiological point of view, and these were sorted depending on the name of the species. Methods and results obtained are discussed. Essential oils and preservatives were ranked by increased efficacy on mould growth. For all the tested molecules, Penicillium species were shown more sensitive than Aspergillus species. However, comparison between the results was difficult because it appeared that the efficiency of active packaging depended greatly on the environmental factors of food such as water activity, pH, temperature, NaCl concentration, the nature, the size, and the mode of application of the films, in addition to the fact that the amount of released antifungal compounds was not constant with time.

  3. Antifungal effect of cumin essential oil alone and in combination with antifungal drugs

    Directory of Open Access Journals (Sweden)

    SAHADEO PATIL

    2015-05-01

    Full Text Available Abstract. Patil S, Maknikar P, Wankhade S, Ukesh C, Rai M. 2015. Antifungal effect of cumin essential oil alone and in combination with antifungal drugs. Nusantara Bioscience 7: 55-59. We report evaluation of antifungal activity of cumin seed oil and its pharmacological interactions when used in combination with some of the widely used conventional antifungal drugs using CLSI broth microdilution, agar disc diffusion and checkerboard microtitre assay against Candida. The essential oil was obtained from cumin seeds using hydrodistillation technique and was later evaluated for the presence of major chemical constituents present in it using gas chromatography and mass spectrometry (GC-MS assay. The GC-MS assay revealed the abundance of γ-terpinene (35.42% followed by p-cymene (30.72%. The agar disc diffusion assay demonstrated highly potent antifungal effect against Candida species. Moreover, the combination of cumin essential oil (CEO with conventional antifungal drugs was found to reduce the individual MIC of antifungal drug suggesting the occurrence of synergistic interactions. Therefore, the therapy involving combinations of CEO and conventional antifungal drugs can be used for reducing the toxicity induced by antifungal drugs and at the same time enhancing their antifungal efficacy in controlling the infections caused due to Candida species.

  4. Antifungal drug resistance to azoles and polyenes.

    Science.gov (United States)

    Masiá Canuto, Mar; Gutiérrez Rodero, Félix

    2002-09-01

    There is an increased awareness of the morbidity and mortality associated with fungal infections caused by resistant fungi in various groups of patients. Epidemiological studies have identified risk factors associated with antifungal drug resistance. Selection pressure due to the continuous exposure to azoles seems to have an essential role in developing resistance to fluconazole in Candida species. Haematological malignancies, especially acute leukaemia with severe and prolonged neutropenia, seem to be the main risk factors for acquiring deep-seated mycosis caused by resistant filamentous fungi, such us Fusarium species, Scedosporium prolificans, and Aspergillus terreus. The still unacceptably high mortality rate associated with some resistant mycosis indicates that alternatives to existing therapeutic options are needed. Potential measures to overcome antifungal resistance ranges from the development of new drugs with better antifungal activity to improving current therapeutic strategies with the present antifungal agents. Among the new antifungal drugs, inhibitors of beta glucan synthesis and second-generation azole and triazole derivatives have characteristics that render them potentially suitable agents against some resistant fungi. Other strategies including the use of high doses of lipid formulations of amphotericin B, combination therapy, and adjunctive immune therapy with cytokines are under investigation. In addition, antifungal control programmes to prevent extensive and inappropriate use of antifungals may be needed.

  5. An antifungal protein from ginger rhizomes.

    Science.gov (United States)

    Wang, Hexiang; Ng, Tzi Bun

    2005-10-14

    There are very few reports on antifungal proteins from rhizomes and there is none from the family of Zingiberaceae. An antifungal protein with a novel N-terminal sequence was isolated from ginger rhizomes utilizing a protocol that involved ion exchange chromatography on DEAE-cellulose, affinity chromatography on Affi-gel blue gel, and fast protein liquid chromatography on Superdex 75. The protein was unadsorbed on DEAE-cellulose and adsorbed on Affi-gel blue gel. It exhibited an apparent molecular mass of 32kDa and exerted antifungal activity toward various fungi including Botrytis cinerea, Fusarium oxysporum, Mycosphaerella arachidicola, and Physalospora piricola.

  6. Antifungal properties of halofumarate esters.

    Science.gov (United States)

    Gershon, H; Shanks, L

    1978-04-01

    Alkyl esters (C1--C4) of the four halofumaric acids were tested for antifungal activity against Candida albicans, Aspergillus niger, Mucor mucedo, and Trichophyton mentagrophytes at pH 5.6 and 7.0 in the absence and presence of 10% beef serum in Sabouraud dextrose agar. The most toxic compound to each organism was: C. albicans, ethyl iodofumarate (0.054 mmole/liter); A. niger, methyl bromofumarate (0.090 mmole/liter); M. mucedo, methyl fluorofumarate (0.037 mmole/liter); and T. mentagrophytes, ethyl iodofumarate (0.020 mmole/liter). The order of overall activity of the six most toxic compounds was: ethyl iodofumarate greater than ethyl chlorofumarate greater than methyl iodofumarate = methyl bromofumarate greater than methyl chlorofumarate greater than bromofumarate.

  7. Collagen-based proteinaceous binder-pigment interaction study under UV ageing conditions by MALDI-TOF-MS and principal component analysis.

    Science.gov (United States)

    Romero-Pastor, Julia; Navas, Natalia; Kuckova, Stepanka; Rodríguez-Navarro, Alejandro; Cardell, Carolina

    2012-03-01

    This study focuses on acquiring information on the degradation process of proteinaceous binders due to ultra violet (UV) radiation and possible interactions owing to the presence of historical mineral pigments. With this aim, three different paint model samples were prepared according to medieval recipes, using rabbit glue as proteinaceus binders. One of these model samples contained only the binder, and the other two were prepared by mixing each of the pigments (cinnabar or azurite) with the binder (glue tempera model samples). The model samples were studied by applying Principal Component Analysis (PCA) to their mass spectra obtained with Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF-MS). The complementary use of Fourier Transform Infrared Spectroscopy to study conformational changes of secondary structure of the proteinaceous binder is also proposed. Ageing effects on the model samples after up to 3000 h of UV irradiation were periodically analyzed by the proposed approach. PCA on MS data proved capable of identifying significant changes in the model samples, and the results suggested different aging behavior based on the pigment present. This research represents the first attempt to use this approach (PCA on MALDI-TOF-MS data) in the field of Cultural Heritage and demonstrates the potential benefits in the study of proteinaceous artistic materials for purposes of conservation and restoration.

  8. Antimycotoxigenic and antifungal activities of Citrullus colocynthis ...

    African Journals Online (AJOL)

    user

    2013-10-23

    Oct 23, 2013 ... Plant extracts and their constituents have a long history as antifungal agents, but their use in biotechnology as preservatives, due to the increasing resistance of ...... Novel taxonomic criteria based on temperature and water.

  9. Early State Research on Antifungal Natural Products

    Directory of Open Access Journals (Sweden)

    Melyssa Negri

    2014-03-01

    Full Text Available Nosocomial infections caused by fungi have increased greatly in recent years, mainly due to the rising number of immunocompromised patients. However, the available antifungal therapeutic arsenal is limited, and the development of new drugs has been slow. Therefore, the search for alternative drugs with low resistance rates and fewer side effects remains a major challenge. Plants produce a variety of medicinal components that can inhibit pathogen growth. Studies of plant species have been conducted to evaluate the characteristics of natural drug products, including their sustainability, affordability, and antimicrobial activity. A considerable number of studies of medicinal plants and alternative compounds, such as secondary metabolites, phenolic compounds, essential oils and extracts, have been performed. Thus, this review discusses the history of the antifungal arsenal, surveys natural products with potential antifungal activity, discusses strategies to develop derivatives of natural products, and presents perspectives on the development of novel antifungal drug candidates.

  10. Antifungal properties of Brazilian cerrado plants

    Directory of Open Access Journals (Sweden)

    Souza Lúcia Kioko Hasimoto e

    2002-01-01

    Full Text Available Ethanolic extracts from leaves of Hyptis ovalifolia, H. suaveolens, H. saxatilis, Hyptidendrum canum, Eugenia uniflora, E. dysenterica, Caryocar brasiliensis and Lafoensia pacari were investigated for their antifungal activity against dermatophytes. The most effective plants were H. ovalifolia and E. uniflora, while Trichophyton rubrum was the most sensitive among the four dermatophytes species evaluated. This study has demonstrated antifungal properties of Brazilian Cerrado plant extracts in "in vitro" assays.

  11. Antifungal activity of five species of Polygala

    Directory of Open Access Journals (Sweden)

    Susana Johann

    2011-09-01

    Full Text Available Crude extracts and fractions of five species of Polygala - P. campestris, P. cyparissias, P. paniculata, P. pulchella and P. sabulosa - were investigated for their in vitro antifungal activity against opportunistic Candida species, Cryptococcus gattii and Sporothrix schenckii with bioautographic and microdilution assays. In the bioautographic assays, the major extracts were active against the fungi tested. In the minimal concentration inhibitory (MIC assay, the hexane extract of P. paniculata and EtOAc fraction of P. sabulosa showed the best antifungal activity, with MIC values of 60 and 30 µg/mL, respectively, against C. tropicalis, C. gattii and S. schenckii. The compounds isolated from P. sabulosa prenyloxycoumarin and 1,2,3,4,5,6-hexanehexol displayed antifungal activity against S. schenckii (with MICs of 125 µg/mL and 250 µg/mL, respectively and C. gattii (both with MICs of 250 µg/mL. Rutin and aurapten isolated from P. paniculata showed antifungal activity against C. gattii with MIC values of 60 and 250 µg/mL, respectively. In the antifungal screening, few of the isolated compounds showed good antifungal inhibition. The compound α-spinasterol showed broad activity against the species tested, while rutin had the best activity with the lowest MIC values for the microorganisms tested. These two compounds may be chemically modified by the introduction of a substitute group that would alter several physico-chemical properties of the molecule, such as hydrophobicity, electronic density and steric strain.

  12. Trends in the utilization of, spending on, and prices for outpatient antifungal agents in US Medicaid programs: 1991-2009.

    Science.gov (United States)

    Desai, Vibha C A; Cavanaugh, Teresa M; Kelton, Christina M L; Guo, Jeff J; Heaton, Pamela C

    2012-10-01

    The incidence of invasive fungal infections (IFIs) has increased substantially in the recent past. Advances in medical technology, including broad-spectrum antibiotics, may increase the risk for fungal infections. Moreover, immunocompromised patients with cancer, HIV/AIDS, and/or transplants are susceptible to IFIs. Meanwhile, superficial fungal infections (SFIs) are common and can be difficult to cure. To provide a historical perspective on a dynamic market with expensive medications, this study describes trends in the utilization of, spending on, and average per-prescription spending on outpatient antifungal medications individually, in classes (for IFIs or SFIs), and overall, by the US Medicaid programs from 1991 to 2009. The publicly available Medicaid State Drug Utilization Data, maintained by the Centers for Medicare & Medicaid Services, were used. Annual prescription counts and reimbursement amounts were calculated for each of the antifungals reimbursed by Medicaid. Average per-prescription spending as a proxy for drug price was calculated by dividing reimbursement by the number of prescriptions. Overall utilization for Medicaid beneficiaries remained steady, with 4.56 million prescriptions in 1991 and 4.51 million in 2009. Expenditures rose from $93.87 million to $143.76 million (in current-year US$) over the same time period. The drop in the utilization of first-generation azoles over the last 5 years of the study period can be explained in part by the movement of dual-eligibles from Medicaid to Medicare Part D and in part to a rise in fungal infections better treated with second-generation azoles or echinocandins. Whereas the average per-prescription price for generic (oral) fluconazole was $8 in 2009, the price per prescription of branded (intravenous) voriconazole was $2178. Overall spending by Medicaid on outpatient antifungal medications increased more slowly than did the growth of the Medicaid programs from 1991 to 2009. However, the utilization of

  13. Effects of varied nitrate and phosphate supply on polysaccharidic and proteinaceous gel particles production during tropical phytoplankton bloom experiments

    Directory of Open Access Journals (Sweden)

    A. Engel

    2015-04-01

    Full Text Available It has been suggested that oxygen minimum zones (OMZ will expand in the tropical oceans as a result of global change with potential consequences for marine element cycling, such as an increase in anaerobic nitrogen loss, resulting in a lower supply of nitrate relative to phosphate to the euphotic zone. So far, the effects of changes in nutrient ratios on organic matter recycling and export fluxes are not well understood. Here, were investigated how different phosphate (Varied P: 0.15–1.58 μmol L−1 or nitrate (Varied N: 1.9–21.9 μmol L−1 concentrations affect the abundance and size distribution of polysaccharidic transparent exopolymer particles (TEP, which are suggested to enhance particle aggregation and export fluxes, and on proteinaceous coomassie stainable particles (CSP, a supposedly good substrate for heterotrophic bacteria. Two series of mesocosm bloom experiments were conducted with natural plankton communities collected from the Eastern Tropical North Atlantic (ETNA close to Cape Verde in October 2012. Until bloom peak, a positive correlation between gel particle abundance and Chl a concentration was determined, linking the release of dissolved gel precursors and the subsequent formation of gel particles to autotrophic production. After bloom peak, gel particle abundance remained stable or even increased, implying a continued partitioning of dissolved into particulate organic matter after biomass production itself ceased. During both experiments, differences between TEP and CSP dynamics were observed; TEP were generally more abundant than CSP. Changes in size distribution indicated aggregation of TEP during the bloom, while newly formed CSP decomposed. Abundance of gel particles clearly increased with nitrate concentration during the second experiment, suggesting that changes in [DIN]:[DIP] ratios can affect gel particle formation with potential consequences for carbon and nitrogen cycling as well as food web dynamics in

  14. A novel proteinaceous cytotoxin from the northern Scyphozoa Cyanea capillata (L.) with structural homology to cubozoan haemolysins.

    Science.gov (United States)

    Lassen, Stephan; Helmholz, Heike; Ruhnau, Christiane; Prange, Andreas

    2011-04-01

    It is well known that jellyfish are producers of complex mixtures of proteinaceous toxins for prey capture and defence. Nevertheless, studies on boreal scyphozoans concerning venom composition and toxic effects are rare. Here the isolation of a novel cytotoxic protein from the fishing tentacle venom of Cyanea capillata (L. 1758) using bioactivity-guided, multidimensional liquid chromatography is described. The crude venom was purified utilising preparative size-exclusion, ion-exchange, and reversed-phase chromatography. The cytotoxicity of resulting chromatographic fractions has been proven by a dye-uptake assay with the human hepatocyte cell line HepG2. The final purification step yielded, among other fractions, a fraction containing a single protein (named CcTX-1) with a molecular weight of its main isoform of 31.17 kDa The purification process leads to an increased cytotoxic activity per protein equivalents and the finally isolated CcTX-1 caused a nearly total loss of cell viability at a protein concentration of 1.3 μg mL⁻¹ corresponding to 0.4 μg/10⁵ cells. De novo sequencing of CcTX-1 was conducted after enzymatic digestion and subsequent matrix-assisted laser desorption ionisation time-of-flight/time-of-flight mass spectrometry (MALDI-ToF/ToF MS/MS). The obtained sequence data provide an approximate 85% description of the amino acid sequence. This sequence information partially matched that of two known haemolytic proteins of two cubozoan species: CaTX-1 from Carybdea alata Reynaud, 1830 and CrTX-1 from Carybdea rastonii Haacke, 1886.

  15. Biological activities of leaves of ethnomedicinal plant, Borassus flabellifer Linn. (Palmyra palm: An antibacterial, antifungal and antioxidant evaluation

    Directory of Open Access Journals (Sweden)

    Prasad G. Jamkhande

    2016-06-01

    Full Text Available Plants contain a variety of phytochemicals that have the ability to exert effect on human body. Among them Borassus flabellifer Linn. is a medicinally important plant. In traditional medicine different parts of plants are being used for their medicinal properties. The methanol extract was obtained from powdered leaves and further fractions were prepared. Antimicrobial potential was investigated using eight pathogenic strains of bacteria and fungi by agar well diffusion method. Broth dilution method was employed to MIC and MMC of active samples and MIC index value was determined. ME was subjected to preliminary phytochemical analysis; and 1,1-diphenyl-2-picrylhydrazyl (DPPH and hydrogen peroxide (H2O2 radical scavenging activity. Phytochemical screening revealed the presence of several phytochemicals. The ME showed dose dependent radical scavenging activity as evidenced by IC50 values for DPPH (40.19 μg/ml and H2O2 (30.92 μg/ml radicals. The inhibition zones and MIC values for bacterial strains were in the range of 10–16 mm and 50–70 μg/ml, respectively. All the samples showed an inhibitory effect on fungal strains with inhibition zone (10–17 mm and MFC (50–70 μg/ml. Samples exhibited diverse patterns of antibacterial and antifungal effects. Among the tested samples, methanol extract and acetone fraction (AF had potent antibacterial and antifungal activities. These results lead to the conclusion that the plant has a broad spectrum antimicrobial and antioxidant activity and could be a potential option for treating various infectious diseases. The strong antioxidant property of methanol extract might be employed in the development of natural antioxidants for agro-food and pharmaceutical industries.

  16. Anti-fungal and anti-bacterial activities of ethanol extracts of selected traditional Chinese medicinal herbs

    Institute of Scientific and Technical Information of China (English)

    Lin Zhang; ngeles Melguizo; Ester Jimnez; Francisca Vicente; Anjaneya S Ravipati; Sundar R Koyyalamudi; Sang Chul Jeong; Narsimha Reddy; John Bartlett; Paul T Smith; Mercedes de la Cruz; Maria Cndida Monteiro

    2013-01-01

    Objective:To evaluate in vitro antimicrobial activities of selected 58 ethno-medicinal plant extracts with a view to assess their therapeutic potential. Methods:A total of 58 traditional Chinese medicinal plants were carefully selected based on the literature review and their traditional use. The antimicrobial activities of ethanol extracts of these medicinal plants were tested against fungi (Aspergillus fumigatus), yeast (Candida albicans), gram-negative (Acinetobacter baumannii and Pseudomonas aeruginosa) and gram-positive bacteria (Staphylococcus aureus). The activities were tested at three different concentrations of 1.00, 0.10 and 0.01 mg/mL. The data was analysed using Gene data Screener program. Results: The measured antimicrobial activities indicated that out of the 58 plant extracts, 15 extracts showed anti-fungal activity and 23 extracts exhibited anti-bacterial activity. Eight plant extracts have exhibited both anti-bacterial and anti-fungal activities. For instance, Eucommia ulmoides, Polygonum cuspidatum, Poria cocos and Uncaria rhyncophylla showed activity against both bacterial and fungal strains, indicating their broad spectrum of activity. Conclusions: The results revealed that the ethanol extracts of 30 plants out of the selected 58 possess significant antimicrobial activities. It is interesting to note that the findings from the current study are consistent with the traditional use. A clear correlation has also been found between the antimicrobial activity and the flavonoid content of the plant extracts which is in agreement with the literature. Hence, the results presented here can be used to guide the selection of potential plant species for the isolation and structure elucidation of novel antimicrobial compounds in order to establish the structure-activity relationship. This in turn is expected to lead the way to the discovery of novel antimicrobial agents for therapeutic use.

  17. Antifungal Activity of Eucalyptus Oil against Rice Blast Fungi and the Possible Mechanism of Gene Expression Pattern

    Directory of Open Access Journals (Sweden)

    Li-Jun Zhou

    2016-05-01

    Full Text Available Eucalyptus oil possesses a wide spectrum of biological activity, including anti-microbial, fungicidal, herbicidal, acaricidal and nematicidal properties. We studied anti-fungal activities of the leaf oil extracted from Eucalyptus. grandis × E. urophylla. Eleven plant pathogenic fungi were tested based on the mycelium growth rates with negative control. The results showed that Eucalyptus oil has broad-spectrum inhibitory effects toward these fungi. Remarkable morphological and structural alterations of hypha have been observed for Magnaporthe grisea after the treatment. The mRNA genome array of M. grisea was used to detect genes that were differentially expressed in the test strains treated by the Eucalyptus oil than the normal strains. The results showed 1919 genes were significantly affected, among which 1109 were down-regulated and 810 were up-regulated (p < 0.05, absolute fold change >2. According to gene ontology annotation analysis, these differentially expressed genes may cause abnormal structures and physiological function disorders, which may reduce the fungus growth. These results show the oil has potential for use in the biological control of plant disease as a green biopesticide.

  18. Spray-dried powders improve the controlled release of antifungal tioconazole-loaded polymeric nanocapsules compared to with lyophilized products

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro, Roseane Fagundes [Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal de Santa Maria, Av. Roraima, 1000, Santa Maria, RS, 97105-900 (Brazil); Motta, Mariana Heldt [Curso de Farmácia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Av. Roraima, 1000, Santa Maria, RS, 97105-900 (Brazil); Härter, Andréia Pisching Garcia; Flores, Fernanda Cramer [Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal de Santa Maria, Av. Roraima, 1000, Santa Maria, RS, 97105-900 (Brazil); Beck, Ruy Carlos Ruver [Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga, 2752, Porto Alegre, RS, 90610-000 (Brazil); Schaffazick, Scheila Rezende [Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal de Santa Maria, Av. Roraima, 1000, Santa Maria, RS, 97105-900 (Brazil); and others

    2016-02-01

    This work aimed to obtain solid formulations from polymeric nanocapsules and nanoemulsions containing tioconazole, a broad spectrum antifungal drug. Two dehydration methods were used: spray-drying and freeze-drying, using lactose as adjuvant (10%, w/v). The liquid formulations had a mean particle size around 206 nm and 182 nm for nanocapsules and nanoemulsions, respectively, and an adequate polydispersity index. Tioconazole content was close to the theoretical amount (1.0 mg/mL). After drying, the content ranged between 98 and 102% with a mean nanometric size of the dried products after redispersion. Scanning electron microscopy showed that the particles are rounded, sphere-shaped for the dried products obtained by spray-drying, and shapeless and irregular shapes for those obtained by freeze-drying. In the microbiological evaluation, all dried products remained active against the yeast Candida albicans when compared to the original systems. The dried products obtained by spray-drying from nanocapsules presented better control of the tioconazole release when compared to the freeze-drying products. - Highlights: • Polymeric nanocapsule suspensions containing tioconazole were submitted to spray-drying and freeze-drying. • Dried products from nanocapsule suspensions were stable for 30 days. • Release studies showed that the dried products presented greater control of drug release compared to the original suspension.

  19. Antifungal drug discovery and development--fourth international summit. 10-11 March 1999, Princeton, New Jersey, USA.

    Science.gov (United States)

    Ryder, N

    1999-05-01

    Genetic and genomic approaches to discovery, selection and evaluation of antifungal targets were extensively discussed by several speakers at this meeting. Experimental targets with early lead compounds available from screening programs include translation (Ribogene Inc), transcription (SCRIPTGEN Pharmaceuticals Inc), and protein geranylgeranylation (Mitotix Inc). Classes of compounds which are more advanced in preclinical evaluation include the sordarins, inhibitors of fungal elongation factor 2 under development by Glaxo Wellcome plc and Merck and Co Inc, and a series of fungicidal peptides originally derived from a domain of the human neutrophil bactericidal permeability-increasing protein (BPI, Xoma Ltd). Preclinical and early clinical data were presented for two compounds: caspofungin (MK-0991, Merck and Co Inc), an echinocandin with a broad-spectrum of activity for parenteral application, and Sch-56592 (Schering-Plough Corp), an orally active triazole. The oral antimycotic, terbinafine (Novartis AG), primarily used in dermatological infections, shows potent synergy with azoles and has potential applications against several serious and drug-resistant fungal pathogens. Amphotericin B, which has long been the gold standard for therapy of life-threatening infections, is now available in several liposomal formulations, including AmBisome (Fujisawa Pharmaceutical Co Ltd) and Abelcet (The Liposome Company Inc) which show a reduced incidence of adverse events.

  20. In vitro and in vivo antifungal profile of a novel and long acting inhaled azole, PC945, on Aspergillus fumigatus infection.

    Science.gov (United States)

    Colley, Thomas; Alanio, Alexandre; Kelly, Steven L; Sehra, Gurpreet; Kizawa, Yasuo; Warrilow, Andrew G S; Parker, Josie E; Kelly, Diane E; Kimura, Genki; Anderson-Dring, Lauren; Nakaoki, Takahiro; Sunose, Mihiro; Onions, Stuart; Crepin, Damien; Lagasse, Franz; Crittall, Matthew; Shannon, Jonathan; Cooke, Michael; Bretagne, Stéphane; King-Underwood, John; Murray, John; Ito, Kazuhiro; Strong, Pete; Rapeport, Garth

    2017-02-21

    The profile of PC945, a novel triazole antifungal, designed for administration via inhalation, has been assessed in a range of in vitro and in vivo studies. PC945 was characterized as a potent, tight-binding inhibitor of Aspergillus fumigatus sterol 14α-demethylase (CYP51A and CYP51B) activity (IC50, 0.23 μM and 0.22 μM, respectively), with characteristic type II azole binding spectra. Against 96 clinically isolated A. fumigatus strains, the MIC values of PC945 ranged from 0.032∼>8 μg/ml, whilst those of voriconazole ranged from 0.064∼4 μg/ml. Spectrophotometric analysis of the effects of PC945 against itraconazole-susceptible and -resistant A. fumigatus growth, yielded IC50 (OD) values between 0.0012∼0.034 μg/ml, whereas voriconazole (0.019∼>1 μg/ml) was less effective than PC945. PC945 was effective against a broad spectrum of pathogenic fungi (MIC ranged from 0.0078∼2 μg/ml) including Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans andRhizopus oryzae (1∼2 isolates each). In addition, when A. fumigatus hyphae or human bronchial cells were treated with PC945, and then washed, PC945 was found to be quickly absorbed into both target and non-target cells and to produce persistent antifungal effects. In temporarily neutropenic immunocompromised mice infected with A. fumigatus intranasally, 50% of the animals survived until day 7 when treated intranasally with PC945 at 0.56 μg/mouse, while posaconazole showed similar effects (44%) at 14 μg/mouse. This profile affirms that topical treatment with PC945 should provide potent antifungal activity in the lung.

  1. Fungal cell-wall lytic enzymes, antifungal metabolite(s) production, and characterization from Streptomyces exfoliatus MT9 for controlling fruit-rotting fungi.

    Science.gov (United States)

    Choudhary, Bharti; Nagpure, Anand; Gupta, Rajinder K

    2014-12-01

    An antifungal actinomycete strain MT9 was isolated from Loktak Lake, Manipur, India and its cultural characteristics, fatty acid methyl ester, 16S rRNA gene analysis suggests that strain MT9 is identical to Streptomyces exfoliatus. Strain MT9 displayed strong and broad-spectrum antagonism towards several fruit-rotting fungi by mycelial growth suppression. Crude fungal cell-wall lytic enzymes, i.e., chitinase, β-1,3-glucanase, and protease produced by S. exfoliatus MT9 were optimally active at pH 8.0 and 50 °C, pH 5.0 and 60 °C, pH 9.0 and 70 °C, respectively. All three mycolytic enzymes had good stability over a wide pH range of 5.0-10.0, with protease being more thermostable than both chitinase and β-1,3-glucanase. Interestingly zymogram analysis revealed that S. exfoliatus MT9 secretes six distinct chitinase isoenzymes with approximate molecular weights of 9.42, 13.93, 27.87, 36.43, 54.95, 103.27 kDa, six active protease isoenzymes with apparent molecular weights of 12.45, 30.20, 37.45, 46.32, 52.46, 131.46 kDa, and an active band of 119.39 kDa as β-1,3-glucanase enzyme. Extracellular fluid and its organic solvent extracts also exhibited inhibitory activity to various fruit-rotting fungi. The MIC value of n-butanol extract was 2-25 µg/ml against tested fruit-rotting fungi. Antifungal secondary metabolite(s) was found to be polyene in nature. To the best of our knowledge, this is the first report on extracellular production of fungal cell-wall lytic enzymes and antifungal metabolites by bioactive S. exfoliatus MT9 under submerged fermentation.

  2. Nutrient-Dependent Efficacy of the Antifungal Protein YvgO Correlates to Cellular Proliferation Rate in Candida albicans 3153A and Byssochlamys fulva H25.

    Science.gov (United States)

    Manns, David C; Churey, John J; Worobo, Randy W

    2014-12-01

    YvgO is a recently characterized antifungal protein isolated from Bacillus thuringiensis SF361 that exhibits a broad spectrum of activity and pH stability. Customized colorimetric metabolic assays based on standard broth microdilution techniques were used to determine the variable tolerance of Byssochlamys fulva H25 and Candida albicans 3153A to YvgO exposure under select matrix conditions impacting cellular proliferation. Normalization of the solution pH after antifungal challenge expanded the available pH range under consideration allowing for a comprehensive in vitro assessment of YvgO efficacy. Indicator susceptibility was examined across an array of elementary growth-modifying conditions, including media pH, incubation temperature, ionic strength, and carbohydrate supplementation. Under suboptimal temperature and pH conditions, the indicator growth rate reduced, and YvgO-mediated susceptibility was attenuated. While YvgO association but not efficacy was somewhat influenced by solution ionic strength, carbohydrate supplementation was shown to be the most influential susceptibility factor, particularly for C. albicans. Although the specific choice of carbohydrate/nutrient supplement dictated the extent of enhanced YvgO efficacy, D-glucose additionally improved the association between antifungal and target. Indeed, when exposed to YvgO under conditions that lead to increased cellular proliferation, both indicators displayed a stronger association and susceptibility to YvgO when compared to carbohydrate-deprived media or suboptimal incubation environments. With further study, YvgO may have the capacity to function as a prophylaxis for food safety and preservation, as well as a pharmaceutical agent against opportunistic fungal pathogens either independently or in combination with other established treatments applied to both livestock and human health concerns.

  3. Silver nanoparticles are broad-spectrum bactericidal and virucidal compounds

    National Research Council Canada - National Science Library

    Lara, Humberto H; Garza-Treviño, Elsa N; Ixtepan-Turrent, Liliana; Singh, Dinesh K

    2011-01-01

    .... Interactions between viral biomolecules and silver nanoparticles suggest that the use of nanosystems may contribute importantly for the enhancement of current prevention of infection and antiviral therapies...

  4. Rufinamide: A Novel Broad-Spectrum Antiepileptic Drug

    OpenAIRE

    Wheless, James W.; Vazquez, Blanca

    2010-01-01

    The last 20 years have witnessed a tremendous explosion in the number of antiepileptic drugs (AEDs) as well as the introduction of AEDS developed for specific epilepsy syndromes. The study of the efficacy and side effect profile of AEDs for unique epilepsy syndromes has allowed neurologists to utilize evidence-based medicine when treating patients. In late 2008, the Food and Drug Administration approved rufinamide for adjunctive use in the treatment of seizures associated with Lennox–Gastaut ...

  5. Rufinamide: a novel broad-spectrum antiepileptic drug

    National Research Council Canada - National Science Library

    Wheless, James W; Vazquez, Blanca

    2010-01-01

    ... has allowed neurologists to utilize evidence-based medicine when treating patients. In late 2008, the Food and Drug Administration approved rufinamide for adjunctive use in the treatment of seizures associated with Lennox-Gastaut syndrome...

  6. Studies on broad spectrum corrosion resistant oxide coatings

    Indian Academy of Sciences (India)

    Someswar Datta

    2001-12-01

    The corrosion resistant oxide coatings, developed and applied by the conventional vitreous enamelling techniques, showed superior resistance to a range of mineral acids at various strengths and temperatures, alkaline solutions, boiling water and chrome plating solutions. These coatings possess considerable abrasion and impact resistance as well as high thermal shock resistance. The properties of the coating system have been studied in detail and found to be strongly dependent on composition and processing parameters. These coatings have been characterized by X-ray diffraction analysis and SEM studies. Some of the coating materials have been found to be biocompatible.

  7. Broad Spectrum Photoelectrochemical Diodes for Solar Hydrogen Generation

    Energy Technology Data Exchange (ETDEWEB)

    Grimes, Craig A.

    2014-11-26

    Under program auspices we have investigated material chemistries suitable for the solar generation of hydrogen by water photoelectrolysis. We have built upon, and extended, our knowledge base on the synthesis and application of TiO2 nanotube arrays, a material architecture that appears ideal for water photoelectrolysis. To date we have optimized, refined, and greatly extended synthesis techniques suitable for achieving highly ordered TiO2 nanotube arrays of given length, wall thickness, pore diameter, and tube-to-tube spacing for use in water photoelectrolysis. We have built upon this knowledge based to achieve visible light responsive, photocorrosion stable n-type and p-type ternary oxide nanotube arrays for use in photoelectrochemical diodes.

  8. Antipneumococcal activity of ceftobiprole, a novel broad-spectrum cephalosporin.

    Science.gov (United States)

    Kosowska, Klaudia; Hoellman, Dianne B; Lin, Gengrong; Clark, Catherine; Credito, Kim; McGhee, Pamela; Dewasse, Bonifacio; Bozdogan, Bülent; Shapiro, Stuart; Appelbaum, Peter C

    2005-05-01

    Ceftobiprole (previously known as BAL9141), an anti-methicillin-resistant Staphylococcus aureus cephalosporin, was very highly active against a panel of 299 drug-susceptible and -resistant pneumococci, with MIC(50) and MIC(90) values (microg/ml) of 0.016 and 0.016 (penicillin susceptible), 0.06 and 0.5 (penicillin intermediate), and 0.5 and 1.0 (penicillin resistant). Ceftobiprole, imipenem, and ertapenem had lower MICs against all pneumococcal strains than amoxicillin, cefepime, ceftriaxone, cefotaxime, cefuroxime, or cefdinir. Macrolide and penicillin G MICs generally varied in parallel, whereas fluoroquinolone MICs did not correlate with penicillin or macrolide susceptibility or resistance. All strains were susceptible to linezolid, quinupristin-dalfopristin, daptomycin, vancomycin, and teicoplanin. Time-kill analyses showed that at 1x and 2x the MIC, ceftobiprole was bactericidal against 10/12 and 11/12 strains, respectively. Levofloxacin, moxifloxacin, vancomycin, and teicoplanin were each bactericidal against 10 to 12 strains at 2x the MIC. Azithromycin and clarithromycin were slowly bactericidal, and telithromycin was bactericidal against only 5/12 strains at 2x the MIC. Linezolid was mainly bacteriostatic, whereas quinupristin-dalfopristin and daptomycin showed marked killing at early time periods. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to yield mutants with high MICs towards this cephalosporin, and single-passage selection showed very low frequencies of spontaneous mutants with breakthrough MICs towards ceftobiprole.

  9. A Lead Compound for the Development of Broad-spectrum ...

    African Journals Online (AJOL)

    NJD

    1. Introduction. The development of untreatable resistant strains of pathogenic ..... rapid screening of antibacterial agents.28 A loopful of culture was taken from the .... Microplate Spectrophotometer, Bio-Rad Laboratories, Hemel. Hempstead ...

  10. Mucin biopolymers as broad-spectrum antiviral agents

    Science.gov (United States)

    Lieleg, Oliver; Lieleg, Corinna; Bloom, Jesse; Buck, Christopher B.; Ribbeck, Katharina

    2012-01-01

    Mucus is a porous biopolymer matrix that coats all wet epithelia in the human body and serves as the first line of defense against many pathogenic bacteria and viruses. However, under certain conditions viruses are able to penetrate this infection barrier, which compromises the protective function of native mucus. Here, we find that isolated porcine gastric mucin polymers, key structural components of native mucus, can protect an underlying cell layer from infection by small viruses such as human papillomavirus (HPV), Merkel cell polyomavirus (MCV), or a strain of influenza A virus. Single particle analysis of virus mobility inside the mucin barrier reveals that this shielding effect is in part based on a retardation of virus diffusion inside the biopolymer matrix. Our findings suggest that purified mucins may be used as a broad-range antiviral supplement to personal hygiene products, baby formula or lubricants to support our immune system. PMID:22475261

  11. The broad spectrum of celiac disease and gluten sensitive enteropathy

    Science.gov (United States)

    MOCAN, OANA; DUMITRAŞCU, DAN L.

    2016-01-01

    The celiac disease is an immune chronic condition with genetic transmission, caused by the intolerance to gluten. Gluten is a protein from cereals containing the following soluble proteins: gliadine, which is the most toxic, and the prolamins. The average prevalence is about 1% in USA and Europe, but high in Africa: 5.6% in West Sahara. In the pathogenesis several factors are involved: gluten as external trigger, genetic predisposition (HLA, MYO9B), viral infections, abnormal immune reaction to gluten. Severity is correlated with the number of intraepithelial lymphocytes, cryptic hyperplasia and villous atrophy, as well as with the length of intestinal involvement. The severity is assessed according to the Marsh–Oberhuber staging. Diagnostic criteria are: positive serological tests, intestinal biopsy, the reversal after gluten free diet (GFD). Beside refractory forms, new conditions have been described, like the non celiac gluten intolerance. In a time when more and more people adhere to GFD for nonscientific reasons, practitioners should be updated with the progress in celiac disease knowledge. PMID:27547052

  12. The broad spectrum of celiac disease and gluten sensitive enteropathy.

    Science.gov (United States)

    Mocan, Oana; Dumitraşcu, Dan L

    2016-01-01

    The celiac disease is an immune chronic condition with genetic transmission, caused by the intolerance to gluten. Gluten is a protein from cereals containing the following soluble proteins: gliadine, which is the most toxic, and the prolamins. The average prevalence is about 1% in USA and Europe, but high in Africa: 5.6% in West Sahara. In the pathogenesis several factors are involved: gluten as external trigger, genetic predisposition (HLA, MYO9B), viral infections, abnormal immune reaction to gluten. Severity is correlated with the number of intraepithelial lymphocytes, cryptic hyperplasia and villous atrophy, as well as with the length of intestinal involvement. The severity is assessed according to the Marsh-Oberhuber staging. Diagnostic criteria are: positive serological tests, intestinal biopsy, the reversal after gluten free diet (GFD). Beside refractory forms, new conditions have been described, like the non celiac gluten intolerance. In a time when more and more people adhere to GFD for nonscientific reasons, practitioners should be updated with the progress in celiac disease knowledge.

  13. Antistaphylococcal activity of ceftobiprole, a new broad-spectrum cephalosporin.

    Science.gov (United States)

    Bogdanovich, Tatiana; Ednie, Lois M; Shapiro, Stuart; Appelbaum, Peter C

    2005-10-01

    Ceftobiprole (formerly BAL9141), the active component of the prodrug BAL5788 (ceftobiprole medocaril), is a novel cephalosporin with expanded activity against gram-positive bacteria. Among 152 Staphylococcus aureus isolates, including 5 vancomycin-intermediate and 2 vancomycin-resistant strains, MIC(50) and MIC(90) values for ceftobiprole were each 0.5 microg/ml against methicillin-susceptible strains and 2 mug/ml against methicillin-resistant strains. Against 151 coagulase-negative staphylococci (including 4 vancomycin-intermediate strains), MIC(50) and MIC(90) values were, respectively, 0.125 microg/ml and 1 microg/ml against methicillin-susceptible and 1 microg/ml and 2 microg/ml against methicillin-resistant strains. Teicoplanin was less active than vancomycin against coagulase-negative strains. Linezolid, quinupristin-dalfopristin, and daptomycin were active against all strains, whereas increased MICs for amoxicillin-clavulanate, cefazolin, minocycline, gentamicin, trimethoprim-sulfamethoxazole, levofloxacin, rifampin, mupirocin, fusidic acid, and fosfomycin were sometimes observed. At 2x MIC, ceftobiprole was bactericidal against 11 of 12 test strains by 24 h. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to select for clones with MICs >4 times those of the parents; the maximum MIC achieved for ceftobiprole after 50 passages (in 1 of 10 strains) was 8 mug/ml. Single-passage selections showed very low frequencies of resistance to ceftobiprole irrespective of genotype or phenotype; the maximal ceftobiprole MIC of recovered clones was 8 mug/ml.

  14. Antianaerobe activity of ceftobiprole, a new broad-spectrum cephalosporin.

    Science.gov (United States)

    Ednie, Lois; Shapiro, Stuart; Appelbaum, Peter C

    2007-05-01

    Agar dilution testing of 463 anaerobes showed most Gram-positive beta-lactamase-negative strains (other than some Clostridium difficile and Peptostreptococcus anaerobius), as well as both beta-lactamase-positive and beta-lactamase-negative strains of Fusobacterium nucleatum, to have ceftobiprole MIC values of Ceftobiprole was less active against beta-lactamase-positive Gram-negative bacilli, especially the members of the Bacteroides fragilis group. Like ceftobiprole, piperacillin was active mainly against beta-lactamase-negative strains, though MIC values for piperacillin were often 1 to 2 dilutions higher than for ceftobiprole. Carbapenems had MIC values < or =4 microg/L against all except some C. difficile and 2 strains of B. fragilis. All strains were susceptible to metronidazole, and all bacteria, except C. difficile and a single Bacteroides distasonis strain, were susceptible to chloramphenicol. Clindamycin resistance was seen in most anaerobe groups, whereas high moxifloxacin MICs were found mainly among the B. fragilis and Prevotella groups, and a few C. difficile and F. nucleatum strains.

  15. Predictive compound accumulation rules yield a broad-spectrum antibiotic

    Science.gov (United States)

    Richter, Michelle F.; Drown, Bryon S.; Riley, Andrew P.; Garcia, Alfredo; Shirai, Tomohiro; Svec, Riley L.; Hergenrother, Paul J.

    2017-05-01

    Most small molecules are unable to rapidly traverse the outer membrane of Gram-negative bacteria and accumulate inside these cells, making the discovery of much-needed drugs against these pathogens challenging. Current understanding of the physicochemical properties that dictate small-molecule accumulation in Gram-negative bacteria is largely based on retrospective analyses of antibacterial agents, which suggest that polarity and molecular weight are key factors. Here we assess the ability of over 180 diverse compounds to accumulate in Escherichia coli. Computational analysis of the results reveals major differences from the retrospective studies, namely that the small molecules that are most likely to accumulate contain an amine, are amphiphilic and rigid, and have low globularity. These guidelines were then applied to convert deoxynybomycin, a natural product that is active only against Gram-positive organisms, into an antibiotic with activity against a diverse panel of multi-drug-resistant Gram-negative pathogens. We anticipate that these findings will aid in the discovery and development of antibiotics against Gram-negative bacteria.

  16. Silver nanoparticles are broad-spectrum bactericidal and virucidal compounds

    Directory of Open Access Journals (Sweden)

    Ixtepan-Turrent Liliana

    2011-08-01

    Full Text Available Abstract The advance in nanotechnology has enabled us to utilize particles in the size of the nanoscale. This has created new therapeutic horizons, and in the case of silver, the currently available data only reveals the surface of the potential benefits and the wide range of applications. Interactions between viral biomolecules and silver nanoparticles suggest that the use of nanosystems may contribute importantly for the enhancement of current prevention of infection and antiviral therapies. Recently, it has been suggested that silver nanoparticles (AgNPs bind with external membrane of lipid enveloped virus to prevent the infection. Nevertheless, the interaction of AgNPs with viruses is a largely unexplored field. AgNPs has been studied particularly on HIV where it was demonstrated the mechanism of antiviral action of the nanoparticles as well as the inhibition the transmission of HIV-1 infection in human cervix organ culture. This review discusses recent advances in the understanding of the biocidal mechanisms of action of silver Nanoparticles.

  17. Development of a Broad-Spectrum Antiviral Agent with Activity ...

    African Journals Online (AJOL)

    Activity Against Herpesvirus Replication and Gene. Expression ... Method: Antiviral activity against Herpes simplex virus type 1 (HSV-1) was determined using thiazolyl ..... Marker; 1 = Vero cells; 2 = HSV-1; 3 = ACV; 4 = H9);. (D) effect of H9 on ...

  18. Wheat-related disorders: A broad spectrum of 'evolving' diseases.

    Science.gov (United States)

    Gasbarrini, Gb; Mangiola, F

    2014-08-01

    Throughout the world, cereals have always been recognized as a fundamental food. Human evolution, through the development of cooking, led to the production of food rich in gluten, in order to take full advantage of the nutritional properties of this food. The result has been that gluten intolerance has arisen only in those populations that developed the art of cooking wheat. It is also recognized that wheat, one of the central elements of the Mediterranean diet, cannot be tolerated in some individuals. Among the wheat-related pathologies, coeliac disease is the best known: it is a chronic inflammatory condition affecting the gastrointestinal tract, which develops in genetically predisposed individuals. The most common manifestation is the malabsorption of nutrients. Recently, another wheat-related disease has appeared: non-coeliac gluten sensitivity, defined as the onset of a variety of manifestations related to wheat, rye and barley ingestion, in patients in whom coeliac disease and wheat allergy have been excluded. In this paper we will explore the damaging power of wheat, analysing the harmful process by which it realizes the onset of clinical manifestations associated with wheat-related disorders.

  19. Enhanced methanol production in plants provides broad spectrum insect resistance.

    Directory of Open Access Journals (Sweden)

    Sameer Dixit

    Full Text Available Plants naturally emit methanol as volatile organic compound. Methanol is toxic to insect pests; but the quantity produced by most of the plants is not enough to protect them against invading insect pests. In the present study, we demonstrated that the over-expression of pectin methylesterase, derived from Arabidopsis thaliana and Aspergillus niger, in transgenic tobacco plants enhances methanol production and resistance to polyphagous insect pests. Methanol content in the leaves of transgenic plants was measured using proton nuclear spectroscopy (1H NMR and spectra showed up to 16 fold higher methanol as compared to control wild type (WT plants. A maximum of 100 and 85% mortality in chewing insects Helicoverpa armigera and Spodoptera litura larvae was observed, respectively when fed on transgenic plants leaves. The surviving larvae showed less feeding, severe growth retardation and could not develop into pupae. In-planta bioassay on transgenic lines showed up to 99 and 75% reduction in the population multiplication of plant sap sucking pests Myzus persicae (aphid and Bemisia tabaci (whitefly, respectively. Most of the phenotypic characters of transgenic plants were similar to WT plants. Confocal microscopy showed no deformities in cellular integrity, structure and density of stomata and trichomes of transgenic plants compared to WT. Pollen germination and tube formation was also not affected in transgenic plants. Cell wall enzyme transcript levels were comparable with WT. This study demonstrated for the first time that methanol emission can be utilized for imparting broad range insect resistance in plants.

  20. Antifungal activity of rice straw extract on some phytopathogenic fungi

    African Journals Online (AJOL)

    user

    2012-09-04

    Sep 4, 2012 ... The antifungal activity of allelochemicals extracted from rice straw on the radial growth rate and the activity of .... laurel, avocado and ginger extracts have strong ... composition and antifungal activity of essential oils of seven.

  1. Epidemiology and antifungal resistance in invasive candidiasis

    Directory of Open Access Journals (Sweden)

    Rodloff AC

    2011-04-01

    Full Text Available Abstract The epidemiology of Candida infections has changed over the last two decades: The number of patients suffering from such infections has increased dramatically and the Candida species involved have become more numerous as Candida albicans is replaced as an infecting agent by various non-C. albicans species (NAC. At the same time, additional antifungal agents have become available. The different Candida species may vary in their susceptibility for these various antifungals. This draws more attention to in vitro susceptibility testing. Unfortunately, several different test methods exist that may deliver different results. Moreover, clinical breakpoints (CBP that classify test results into susceptible, intermediate and resistant are controver- sial between CLSI and EUCAST. Therefore, clinicians should be aware that interpretations may vary with the test system being followed by the microbiological laboratory. Thus, knowledge of actual MIC values and pharmacokinetic properties of individual antifungal agents is important in delivering appropriate therapy to patients

  2. Interaction between larval α-amylase of the tomato leaf miner, Tuta absoluta Meyrick (Lepidoptera: Gelechiidae and proteinaceous extracts from plant seeds

    Directory of Open Access Journals (Sweden)

    Esmaeily Mojtaba

    2015-07-01

    Full Text Available The tomato leaf miner, Tuta absoluta Meyrick (Lepidoptera: Gelechiidae, is one of the most destructive pest of solanaceae and it prefers tomato (Solanum lycopersicum L.. The aim of the current study was to investigate the effects of a wide range of seed proteinaceous extracts from different plant families against T. absoluta α-amylase activity. The effect of pH on the inhibitory activity of seed extracts showed that seed extracts of amaranth along with a wheat cultivar (Alvand, Aflak, Sarvdasht, Alborz, and Kavir produced more than a 50% inhibition of the insect amylase. Aflak wheat seed extract at 10 μg, inhibited 81% of the insect amylase. This percent was the highest inhibition achieved. The other proteinaceous seed extracts had a lower effect on the enzymatic activity. Probit analysis showed that Aflak, Kavir, Alborz, Alvand, Sarvdasht, and amaranth inhibited the amylase activity with an I50 of 1.94, 3.24, 3.46, 3.31, 4.97, and 15.39 μg, respectively. The effect of pH on the inhibition of the α-amylase showed the highest inhibition of Amaranth and wheat, at a pH value of 8.0, which corresponds to the pH of the insect’s gut. Gel electrophoresis assays confirmed the spectrophotometric assays showing that the α-amylase of the insect gut was affected by the presence of the seed extracts. In the gel assay, a high concentration (14 μg protein of amaranth proteinaceous seed extract greatly decreased the intensity of the α-amylase band. A high concentration of the Aflak wheat cultivar (10 μg protein caused the disappearance of the amylase band in the gel. Thus, it is concluded that the physiochemical environment of the insect gut affects the interaction between digestive α-amylase and the metabolites. The experiments showed that seed proteinaceous extracts from non-host plant species, produced more inhibition of the insect amylase when compared to the host plant species. It appears that with evolution, adaptation took place so that insect

  3. Synthesis, Antifungal Activities and Qualitative Structure Activity Relationship of Carabrone Hydrazone Derivatives as Potential Antifungal Agents

    Directory of Open Access Journals (Sweden)

    Hao Wang

    2014-03-01

    Full Text Available Aimed at developing novel fungicides for relieving the ever-increasing pressure of agricultural production caused by phytopathogenic fungi, 28 new hydrazone derivatives of carabrone, a natural bioactive sesquisterpene, in three types were designed, synthesized and their antifungal activities against Botrytis cinerea and Colletotrichum lagenarium were evaluated. The result revealed that all the derivatives synthesized exhibited considerable antifungal activities in vitro and in vivo, which led to the improved activities for carabrone and its analogues and further confirmed their potential as antifungal agents.

  4. Construction and Identification of Antibodies 2F5 and 4E10 Target Gene Vectors with the Neutralization of Anti-HIV Broad Spectrum%含抗HIV广谱中和抗体2F5、4E10靶基因载体的构建及鉴定

    Institute of Scientific and Technical Information of China (English)

    王晶妍; 张煜; 王珂; 王建英

    2012-01-01

    目的:构建含HIV gp120,gp41序列中广谱中和抗体2F5,4E10作用靶基因的载体并进行鉴定,为后期重组载体表达产物诱导产生中和抗体及抗HIV亚单位疫苗的研究奠定基础.方法:根据NCBI中HIV gp120,gp41基因序列中可与2F5、4E10结合的区域设计引物并进行PCR反应,将PCR得到的目的片段插入到载体pET28a中,对重组载体进行PCR鉴定、酶切鉴定及DNA测序.结果:PCR鉴定、酶切鉴定及DNA测序结果证实重组载体构建成功.结论:成功构建了含HIV gp120,gp41序列中广谱中和抗体2F5,4E10作用靶基因的载体.%Objective Antibodies 2F5 and 4E10 target gene vectors with the neutralization of anti-HIV broad spectrum were constructed and identified. This will certainly lay the foundation for future research of neutralizing antibodies from recom-binanl vector products in expression and induction and anti-HIV subunit vaccine. Method Primers were designed and PCR was conducted according to the binding region of the HIV gp120, gp41 gene sequences in NCBI and the 2F5 , 4E10. Then the target fragments from PCR were inserted into the vector pET28a. In the end. PCR, restriction enzyme digestion and DNA sequencing were performed for the recombinant vectors. The results; PCR, restriction enzyme digestion and DNA sequencing confirmed that the recombinant vector were successfully constructed. The conclusion; The construction of vectors of broad-spectrum neutralizing antibodies 2F5, 4E10 target genes containing HIV gp120. gp41 gene sequences was successfully conducted in this paper.

  5. Design,Synthesis and Antifungal Activity of Novel Triazole Derivatives

    Institute of Scientific and Technical Information of China (English)

    Chun Quan SHENG; Wan Nian ZHANG; Hai Tao JI; Yun Long SONG; Min ZHANG; You Jun ZHOU; Jia Guo LU; Jü ZHU

    2004-01-01

    Twenty-one 1-(1H-1,2,4-triazolyl)-2-(2,4-diflurophenyl)-3-(4-substituted-1- piperazinyl)-2-propanol derivatives were designed and synthesized,on the basis of the active site of lanosterol 14(-demethylase.In vitro antifungal activities showed that some of the target compounds had higher antifungal activity and broader antifungal spectrum than fluconazole.

  6. Human mycoses and advances in antifungal therapy.

    Science.gov (United States)

    Fromtling, R A

    2001-04-01

    The 11th Focus on Fungal Infections meeting was held in Washington, D.C., U.S.A., March 1416, 2001. At the conference, there were well-attended sessions that focused on the pathogenesis and therapy of fungal disease. This report focuses on new information on fungal incidence and pathogenesis as well as on the in vitro and clinical experience of established antifungal drugs (fluconazole, itraconazole, amphotericin B, liposomal formulations of amphotericin B, terbinafine) and the newer antifungal compounds approved for use (e.g., caspofungin) and in development (the new-generation azoles: voriconazole, posaconazole, ravuconazole, and the candins, micafungin and anidulafungin).

  7. Antifungal agents in neonates: issues and recommendations.

    Science.gov (United States)

    Almirante, Benito; Rodríguez, Dolors

    2007-01-01

    Fungal infections are responsible for considerable morbidity and mortality in the neonatal period, particularly among premature neonates. Four classes of antifungal agents are commonly used in the treatment of fungal infections in pediatric patients: polyene macrolides, fluorinated pyrimidines, triazoles, and echinocandins. Due to the paucity of pediatric data, many recommendations for the use of antifungal agents in this population are derived from the experience in adults. The purpose of this article was to review the published data on fungal infections and antifungal agents, with a focus on neonatal patients, and to provide an overview of the differences in antifungal pharmacology in neonates compared with adults. Pharmacokinetic data suggest dosing differences in children versus adult patients with some antifungals, but not all agents have been fully evaluated. The available pharmacokinetic data on the amphotericin B deoxycholate formulation in neonates exhibit considerable variability; nevertheless, the dosage regimen suggested in the neonatal population is similar to that used in adults. More pharmacokinetic information is available on the liposomal and lipid complex preparations of amphotericin B and fluconazole, and it supports their use in neonates; however, the optimal dosage and duration of therapy is difficult to establish. All amphotericin-B formulations, frequently used in combination with flucytosine, are useful for treating disseminated fungal infections and Candida meningitis in neonates. Fluconazole, with potent in vitro activity against Cryptococcus neoformans and almost all Candida spp., has been used in neonates with invasive candidiasis at dosages of 6 mg/kg/day, and for antifungal prophylaxis in high-risk neonates. There are limited data on itraconazole, voriconazole, and posaconazole use in neonates. Caspofungin, which is active against Candida spp. and Aspergillus spp., requires higher doses in children relative to adults, and dosing is

  8. Characterization of Antifungal Activity and Nail Penetration of ME1111, a New Antifungal Agent for Topical Treatment of Onychomycosis

    OpenAIRE

    Tabata, Yuji; Takei-Masuda, Naomi; Kubota, Natsuki; Takahata, Sho; Ohyama, Makoto; Kaneda, Kaori; Iida, Maiko; Maebashi, Kazunori

    2016-01-01

    Fungal nail infection (onychomycosis) is a prevalent disease in many areas of the world, with a high incidence approaching 23%. Available antifungals to treat the disease suffer from a number of disadvantages, necessitating the discovery of new efficacious and safe antifungals. Here, we evaluate the in vitro antifungal activity and nail penetration ability of ME1111, a novel antifungal agent, along with comparator drugs, including ciclopirox, amorolfine, terbinafine, and itraconazole. ME1111 ...

  9. Characterization of Antifungal Activity and Nail Penetration of ME1111, a New Antifungal Agent for Topical Treatment of Onychomycosis

    OpenAIRE

    Tabata, Yuji; Takei-Masuda, Naomi; Kubota, Natsuki; Takahata, Sho; Ohyama, Makoto; Kaneda, Kaori; Iida, Maiko; Maebashi, Kazunori

    2016-01-01

    Fungal nail infection (onychomycosis) is a prevalent disease in many areas of the world, with a high incidence approaching 23%. Available antifungals to treat the disease suffer from a number of disadvantages, necessitating the discovery of new efficacious and safe antifungals. Here, we evaluate the in vitro antifungal activity and nail penetration ability of ME1111, a novel antifungal agent, along with comparator drugs, including ciclopirox, amorolfine, terbinafine, and itraconazole. ME1111 ...

  10. Design, synthesis and antifungal activity of novel triazole derivatives%新型三唑类化合物的设计、合成和抗真菌活性研究

    Institute of Scientific and Technical Information of China (English)

    李洋洋; 刘华; 刘宏; 张永强; 张万年; 盛春泉

    2013-01-01

    目的 基于唑类药物合理优化的分子设计模型,设计新型三唑类化合物,并测试其对常见致病真菌的抑制活性.方法 采用环氧化物开环法合成目标化合物,通过1H NMR和MS确证其化学结构,经微量液基豨释法测试体外抗真菌活性.结果 合成了2个含三唑酮侧链的新型唑类化合物,它们均显示了优秀的广谱抗真菌活性.结论 目标化合物对白色念珠菌的活性优于对照药氟康唑和酮康唑,值得进一步深入构效关系研究.%Objective To design the novel triazole derivatives and test their in vitro antifungal activities on the basis of the molecular design model for rational optimization of azole drugs. Methods Ring-open reaction of the oxiranes was used to synthesize the target compounds, whose chemical structures were confirmed by 'H NMR and MS. Serial dilution method was used to determine the in vitro antifungal activities. Results Two novel azole compounds containing trizaolone side chains were synthesized which showed excellent and broad-spectrum antifungal activity. Conclusion The targeted compounds showed better antifungal activity against Candida al-bicans than the positive drugs fluconazole and ketoconazole, which was worth to further investigate the structure-activity relationship.

  11. In vitro antifungal susceptibility of coelomycete agents of black grain eumycetoma to eight antifungals

    NARCIS (Netherlands)

    Ahmed, Sarah Abdalla; de Hoog, G Sybren; Stevens, David A; Fahal, Ahmed H; van de Sande, Wendy W J

    2015-01-01

    Fungal mycetoma (eumycetoma) represents one of the most difficult infections to appropriately manage. The current recommended treatment is based on extensive surgical debridement combined with prolonged antifungal therapy with ketoconazole or itraconazole. Despite the different phylogenetic

  12. Classification of influenza A virus and its value for research of universal influenza vaccine and broad-spectrum neutralization antibody%甲型流感病毒分类与通用流感疫苗及广谱中和活性抗体的研究

    Institute of Scientific and Technical Information of China (English)

    蒋露芳; 居丽雯; 姜庆五

    2011-01-01

    Influenza is a great harm contagious disease for human. Vaccination is considered to be the most effective means to prevent influenza. For the problems of existing vaccine on timeliness and effectiveness,universal influenza vaccine,which can preclude all the influenza virus and induce duration protective immunity, has been a hot research. Meanwhile, the broad-spectrum neutralization antibody against all influenza A viruses is also the current focus. All these have made the request to explore applicable classification of influenza A virus.%流感是对人类危害极大的传染病,疫苗接种被认为是预防流感的最有效手段.为解决流感病毒变异导致现有疫卣时效性与有效性的问题,研制能够预防所有流感病毒毒株、可诱导持久保护性免疫的通用流感疫苗一直是流感研究的热点,同时,能中和所有甲型流感病毒的广谱中和活性抗体的研究也已成为目前关注的重点,因此对甲型流感病毒分类研究也提出了相应的要求.

  13. Cell wall proteinaceous components in isolates of Candida albicans and non-albicans species from HIV-infected patients with oropharyngeal candidiasis.

    Science.gov (United States)

    López-Ribot, J L; Kirkpatrick, W R; McAtee, R K; Revankar, S G; Patterson, T F

    1998-09-01

    Oropharyngeal candidiasis (OPC) remains a common opportunistic infection in HIV-infected patients. Candida albicans is the most frequent causative agent of OPC. However, non-albicans spp. are being increasingly isolated. Candidal cell wall proteins and mannoproteins play important roles in the biology and patogenesis of candidiasis. In the present study, we have analyzed the proteinaceous components associated with cell wall extracts from C. albicans, Candida tropicalis, Candida pseudotropicalis, Candida krusei, Candida glabrata, Candida parapsilosis, Candida guilliermondii and Candida rugosa obtained from HIV-infected patients with recurrent OPC. Cell wall proteinaceous components were extracted with beta-mercaptoethanol and analyzed using electrophoresis, immunoblotting (with antisera generated against C. albicans cell wall components, and with serum samples and oral saline rinses from patients with OPC), and lectin-blotting (concanavalin A) techniques. Numerous molecular species were solubilized from the various isolates. Major qualitative and quantitative differences in the polypeptidic and antigenic profiles associated with the cell wall extracts from the different Candida spp. were discernible. Some of the antibody preparations generated against C. albicans cell wall components were able to recognize homologous materials present in the extracts from non-albicans spp. Information on cell wall antigens of Candida species may be important in the therapy and prevention of HIV-related OPC.

  14. SHORT COMMUNICATION EVALUATION OF ANTIFUNGAL AND ...

    African Journals Online (AJOL)

    Preferred Customer

    new antifungal/antibacterial compounds which may ultimately be used as drugs. Literature ... industrial, agrochemical and pharmaceutical [4-7]. Some of ..... Chang, R.S.; Ding, L.; Chen, G.Q; Pan, Q.C.; Zhao, Z.L.; Smith, K.M. Soc. Expt. Biol.

  15. Lipid-based antifungal agents: current status.

    Science.gov (United States)

    Arikan, S; Rex, J H

    2001-03-01

    Immunocompromised patients are well known to be predisposed to developing invasive fungal infections. These infections are usually difficult to diagnose and more importantly, the resulting mortality rate is high. The limited number of antifungal agents available and their high rate of toxicity are the major factors complicating the issue. However, the development of lipid-based formulations of existing antifungal agents has opened a new era in antifungal therapy. The best examples are the lipid-based amphotericin B preparations, amphotericin B lipid complex (ABLC; Abelcet), amphotericin B colloidal dispersion (ABCD; Amphotec or Amphocil), and liposomal amphotericin B (AmBisome). These formulations have shown that antifungal activity is maintained while toxicity is reduced. This progress is followed by the incorporation of nystatin into liposomes. Liposomal nystatin formulation is under development and studies of it have provided encouraging data. Finally, lipid-based formulations of hamycin, miconazole, and ketoconazole have been developed but remain experimental. Advances in technology of liposomes and other lipid formulations have provided promising new tools for management of fungal infections.

  16. Fluconazole prophylaxis for fungal infection in high risk preterm infants receiving broad-spectrum antibiotics over 10 days%氟康唑预防高危因素早产儿广谱抗生素使用后真菌感染的效果及安全性

    Institute of Scientific and Technical Information of China (English)

    陈涵强; 杨文庆; 杨长仪

    2010-01-01

    Objective To evaluate the benefits of fluconazole prophylaxis in preventing fungal infection in high risk premature infants using broad-spectrum antibiotics consecutively more than 10 days. Methods From October 2007 to September 2009, 164 preterm infants in high risk of fungal infection using broad-spectrum antibiotics consecutively more than 10 days were eligible for the study. Eighty-five infants,hospitalized from October 2008 to September 2009, were in the fluconazole group and were administered intravenously 3 mg/kg fluconazole every day for three days since the 11th day of antibiotic course. The other 79 infants, hospitalized from October 2007 to September 2008, were in the control group with no fluconazole administration. Fungal infection and colonizations and common complications were observed in the two groups. Results Fungal infection occured in six infants in the control group and none in the fluconazole group(χ2 = 4. 719,P = 0.03). There were no significant differences between the two groups in fungal colonization(χ2 =0. 175,P = 0. 675). No adverse effects of fluconazole therapy were documented. Conclusions Fluconazole prophylaxis may reduce the risk for fungal infection in high risk preterm infants.%目的 评估氟康唑对连续使用广谱抗生素10 d以上,且具有高危因素的早产儿发生侵袭性真菌感染的预防作用.方法 以2007年10月至2009年9月间入院,具有真菌感染高危因素并连续使用广谱抗生素10 d以上的164例早产儿为研究对象,将2008年10月至2009年9月入院的符合条件的85例早产儿作为预防组.予氟康唑3 mg/(kg·次)静脉滴注,每天1次,连续用3 d;将2007年10月至2008年9月入院的符合条件的79例早产儿作为对照组,不应用氟康唑预防.观察两组真菌感染和定植情况,以及常见并发症.结果 预防组无一例发生侵袭性真菌感染,对照组发生6例深部真菌感染,差异有统计学意义(χ2=4.719,P=0.03);预防组真菌定植11

  17. Application of broad-spectrum humanized neutralizing monoclonal antibodies to influenza A virus in prevention and treatment of influenza%广谱全人源化甲型流感病毒中和抗体在流感预防与治疗中的应用

    Institute of Scientific and Technical Information of China (English)

    高灵茜; 杨利

    2013-01-01

    针对多个亚型甲型流感病毒的广谱中和性单克隆抗体(monoclonalantibody,mAb)是极具潜力的新型而有效的流感防治手段.抗流感病毒血凝素(hemagglutinin,HA)的保护性mAb,无论通过主动免疫还是被动免疫,均具有很好的效果.迄今,已有不少甲型流感病毒广谱中和性mAb被开发出来.尽管这些mAb具备临床应用潜能以及作为研制新型疫苗(抗独特型抗体疫苗)的可能,但仅有几种HA mAb对人类流感防治真正有效.此文主要对能高效识别多个亚型HA的人源化甲型流感病毒mAb做一综述.%Broad-spectrum neutralizing monoclonal antibodies (mAbs) against different subtypes of influenza A viruses are potential tools to prevent and treat influenza.Protective mAbs to influenza hemagglutinin (HA) have good results by passive and active immunization.So far,a number of mAbs against influenza HA have been developed.But only few of them are effective for influenza prevention and treatment.In this article,the human mAbs which can recognize divergent influenza isolates are reviewed.

  18. In vitro antifungal susceptibility of coelomycete agents of black grain eumycetoma to eight antifungals.

    Science.gov (United States)

    Ahmed, Sarah Abdalla; de Hoog, G Sybren; Stevens, David A; Fahal, Ahmed H; van de Sande, Wendy W J

    2015-04-01

    Fungal mycetoma (eumycetoma) represents one of the most difficult infections to appropriately manage. The current recommended treatment is based on extensive surgical debridement combined with prolonged antifungal therapy with ketoconazole or itraconazole. Despite the different phylogenetic positions of black-grain eumycetoma species, they are all treated with the same antifungal agents. The in vitro antifungal susceptibility of coelomycetous eumycetoma agents in the order of Pleosporales presently is largely unknown. Here we determined the in vitro activity of eight antifungal agents against seven species causing human eumycetoma using the Sensititre YeastOne method. High minimum inhibitory concentrations (MICs) were found with fluconazole, caspofungin, flucytosine, and amphotericin B. Voriconazole and posaconazole were found to be active against all species tested. Of the species included in the investigation, MICs of Medicopsis romeroi differed from the rest of the mycetoma causative agents belonging to the order of the Pleosporales. We found significantly lower MICs for amphotericin B and significantly higher MICs for fluconazole, ketoconazole, and itraconazole against this species. Our results emphasised that identification of black grain mycetoma agent is important as well as performing susceptibility testing before starting of antifungal treatment. © The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  19. An antifungal peptide from the coconut.

    Science.gov (United States)

    Wang, H X; Ng, T B

    2005-12-01

    A chromatographic procedure consisting of ion exchange chromatography on DEAE-cellulose, affinity chromatography on Affi-gel blue gel, ion exchange chromatography on CM-cellulose, and gel filtration by fast performance liquid chromatography on Supedex 75 was utilized to isolate a 10 kDa antifungal peptide from coconut flesh. The peptide was unadsorbed on DEAE-cellulose, but adsorbed on Affi-gel blue gel and CM-cellulose. It displayed antifungal activity against Fusarium oxysporum, Mycosphaerella arachidicola and Physalospora piricola. The IC50 values of its inhibitory activities on mycelial growth in M. arachidicola and HIV-1 reverse transcriptase activity were respectively 1.2 and 52.5 microM.

  20. Tolerability and safety of antifungal drugs

    Directory of Open Access Journals (Sweden)

    Francesco Scaglione

    2013-08-01

    Full Text Available When treating critically ill patients, as those with fungal infections, attention should be focused on the appropriate use of drugs, especially in terms of dose, safety, and tolerability. The fungal infection itself and the concomitant physiological disorders concur to increase the risk of mortality in these patients, therefore the use of any antifungal agent should be carefully evaluated, considering both the direct action on the target fungus and the adverse effects eventually caused. Among antifungal drugs, echinocandins have the greatest tolerability. In fact, unlike amphotericin B, showing nephrotoxicity, and azoles, which are hepatotoxic, the use of echinocandins doesn’t result in major adverse events.http://dx.doi.org/10.7175/rhc.v4i2s.873

  1. Antifungal Efficacy of Myrtus communis Linn

    OpenAIRE

    Sadeghi Nejad; Erfani Nejad; Yusef Naanaie; Zarrin

    2014-01-01

    Background The ethanolic extract of Myrtus communis Linn. leaves was assayed in vitro as a growth inhibitor against opportunistic fungi such as Candida and Aspergillus species. Myrtus communis Linn. (Family, Myrtaceae) is an aromatic evergreen shrub or small tree. It is native to the Mediterranean region. Objectives This study aimed to assess antifungal activity (in vitro) of the ethanolic extracts of Myrtus communis leaves as a g...

  2. Antifungal Drug Resistance - Concerns for Veterinarians

    Directory of Open Access Journals (Sweden)

    Bharat B. Bhanderi

    2009-10-01

    Full Text Available In the 1990s, there were increased incidences of fungal infectious diseases in human population which might be due to increase in immunosuppressive diseases. But the major concern was increase in prevalence of resistance to antifungal drugs which were reported both in the fungal isolates of human beings and that of animal origin. In both animals and human beings, resistance to antimicrobial agents has important implications for morbidity, mortality and health care costs, because resistant strains are responsible for bulk of infection in animals and human beings, and large number of antimicrobial classes offers more diverse range of resistance mechanisms to study and resistance determinants move into standard well-characterized strains that facilitates the detailed study of molecular mechanisms of resistance in microorganisms. Studies on resistance to antifungal agents has been lagging behind that of antibacterial resistance for several reasons, the foremost reason might be fungal agents were not recognized as important animal and human pathogens, until relatively in recent past. But the initial studies of antifungal drug resistance in the early 1980s, have accumulated a wealth of knowledge concerning the clinical, biochemical, and genetic aspects of this phenomenon. Presently, exploration of the molecular aspects for antifungal drug resistance has been undertaken. Recently, the focus was on several points like developing a more detailed understanding of the mechanisms of antimicrobial resistance, improved methods to detect resistance when it occurs, methods to prevent the emergence and spread of resistance and new antimicrobial options for the treatment of infections caused by resistant organisms. [Vet. World 2009; 2(5.000: 204-207

  3. [Antifungal mechanism of Bacillus marinus B-9987].

    Science.gov (United States)

    Gao, Wei; Tian, Li; Zhou, Junying; Shi, Zhenping; Zheng, Li; Cui, Zhisong; Li, Yuanguang

    2009-11-01

    We studied the antifungal effect of the metabolite BMME-1 from Bacillus marinus B-9987, to reveal its antifungal mechanism. The permeability of the Alternaria solani was tested by spectrophotometer after the treating the crude extracts of B-9987. The composition of cell wall and the sterol components of the fungal plasmalemma of Alternaria solani were analyzed with Infrared Spectrum and GC-MS, respectively. We found that the metabolites of B-9987 had strong antifungal activity with MIC50 and MFC value being 6.2mg/L and 50mg/L. The absorbance in extracellular fluid detection showed that the tegument of the fungi was impaired. The detection of glucan and chitin indicated the change in the structure of the cell wall. The absorption peak of the carbon-hydrogen bond, beta-glucosidic bond, carbon--oxygen bond was attenuated but the hydroxyl, carbonyl absorption was enhanced on the contrary. There were only one peak change in chitin chromatogram on the absorption of amide linkage comparing to the control. These changes on the structure may affect the stability of the fungal cell wall. Ergosterol was the predominant component of sterol with the proportion of 62.52 +/- 3.31% in control cells, but showed a decline during treatment with BMME-1 at a concentration of 56.36 +/- 2.52%. Accumulation of coprostanol, the precursor of ergosterol, was found in the test. From the result we can conclude that the antifungal mechanism of the crude extracts was interfering of ergosterol synthesis resulting in the change on permeability, and also mainly changed the structure of the cell wall, mainly acting on the glucan synthesis.

  4. Antifungal activity of streptomycetes isolated bentonite clay

    Directory of Open Access Journals (Sweden)

    V. P. Shirobokov

    2016-12-01

    Full Text Available Aim. To investigate the biological activity of streptomycetes, isolated from Ukrainian bentonite clay. Methods. For identification of the investigated microorganisms there were used generally accepted methods for study of morpho-cultural and biochemical properties and sequencing of 16Ѕ rRNA producer. Antagonistic activity of the strain was determined by agar diffusion and agar block method using gram-positive, gram-negative microorganisms and fungi. Results. Research of autochthonous flora from bentonite clay of Ukrainian various deposits proved the existence of stable politaxonomic prokaryotic-eukaryotic consortia there. It was particularly interesting that the isolated microorganisms had demonstrated clearly expressed antagonistic properties against fungi. During bacteriological investigation this bacterial culture was identified like representative of the genus Streptomyces. Bentonite streptomycetes, named as Streptomyces SVP-71, inagar mediums (agar block method inhibited the growth of fungi (yeast and mold; zones of growth retardation constituted of 11-36 mm, and did not affect the growth of bacteria. There were investigated the inhibitory effects of supernatant culture fluid, ethanol and butanol extracts of biomass streptomycetes on museum and clinical strains of fungi that are pathogenic for humans (Candida albicans, C. krusei, C. utilis, C. parapsilosis, C. tropicalis, C. kefir, S. glabrata, C. lusitaniae, Aspergillus niger, Mucor pusillus, Fusarium sporotrichioides. It has been shown that research antifungal factor had 100% of inhibitory effect against all fungi used in experiments in vitro. In parallel, it was found that alcohol extracts hadn’t influence to the growth of gram-positive and gram-negative bacteria absolutely. It was shown that the cultural fluid supernatant and alcoholic extracts of biomass had the same antagonistic effect, but with different manifestation. This evidenced about identity of antifungal substances

  5. Antifungal Efficacy of Myrtus communis Linn

    Directory of Open Access Journals (Sweden)

    Sadeghi Nejad

    2014-08-01

    Full Text Available Background The ethanolic extract of Myrtus communis Linn. leaves was assayed in vitro as a growth inhibitor against opportunistic fungi such as Candida and Aspergillus species. Myrtus communis Linn. (Family, Myrtaceae is an aromatic evergreen shrub or small tree. It is native to the Mediterranean region. Objectives This study aimed to assess antifungal activity (in vitro of the ethanolic extracts of Myrtus communis leaves as a growth inhibitor against 24 clinical isolates of Candida, including C. albicans, C. glabrata, and C. tropicalis also three species of Aspergillus, including A. niger, A. flavus, and A. terreus. Materials and Methods The ethanolic extract of myrtle leaves was prepared by maceration method and minimal inhibitory concentration (MIC of Myrtus communis leaves extract was determined by agar-well diffusion technique. Amphotericin B and clotrimazole were used as the positive control in this assay. Results The minimal inhibitory concentration (MICs values of Myrtus communis leaves extract ranged 0.625-5.0 µg/µL and 5-40 µg/µL against tested Candida spp. and Aspergillus spp., respectively. Conclusions Results revealed that the ethanolic extract of Myrtus communis leaves have antifungal potency against both pathogenic tested fungi, and it can be used as a natural antifungal agent.

  6. Antifungal activity of Terminalia superba (combretaceae

    Directory of Open Access Journals (Sweden)

    SIAKA Sohro

    2015-04-01

    Full Text Available The aim of the present study was to optimize the anticandidosic activities of Terminalia superba (TEKAM4 and the identification of major compounds present in the most active chromatographic fraction. The hydroethanolic extract TEKAM4-X0 was prepared by homogenization employing a blender. Two derivatives extracts of TEKAM4-X0 (X1-1 and X1-2 were obtained by a liquid/liquid partition of TEKAM4-X0 in a mixture of hexane and water (v/v. Three chromatographic fractions (F1, F2 and F3 from X1-2 were separated by means of Sephadex-LH20 gel filtration chromatography. All the extracts were incorporated to Sabouraud according to the agar slanted double dilution method. Ketoconazole was used as standards for antifungal assay. The entire fractions were tested on the previously prepared medium culture containing 1000 cells of C. albicans. Antifungal activity was determined by evaluating antifungal parameters values (MFC and IC50. Lastly, the structures of 2 isolated compounds were elucidated by combination of Flash chromatography and spectroscopic methods, including MS, and multiple stage RMN experiments.

  7. Antifungal ellagitannin isolated from Euphorbia antisyphilitica Zucc

    Institute of Scientific and Technical Information of China (English)

    Juan; Ascacio-Valdés; Edgardo; Burboa; Antonio; F; Aguilera-Carbo; Mario; Aparicio; Ramón; Pérez-Schmidt; Raúl; Rodríguez; Cristóbal; N; Aguilar

    2013-01-01

    Objective:To study antifungal activity of a new ellagitannin isolated from the plant residues of Euphorbia antisyphilitica(E.antisyphilitica)Zucc in the wax extraction process.Methods:An extract was prepared from dehydrated and pulverized residues and fractionated by liquid chromatography on Amberilte XAD-16,until obtained an ellagitannin-rich ethanolic fraction which was treated by rotaevaporation to recover the ellagitannin as fine powder.An aqueous solution was prepared and treated through ionic exchange liquid chromatography(Q XL)and gel permeation chromatography(G 25).The ellagitannin-rich fraction was thermogravimetrically evaluated(TGA and DTA)to test the thermo-stability of ellagic acid(monomeric unit).Then ellagitannin powder was analyzed by infrared spectrospcopy to determinate the functional groups and.also mass spectroscopy was used to determine the molecular ion.Results:The principal functional groups of ellagitannin were determined,the molecular weight was 860.7 g/mol;and an effective antifungal activity against phytopathogenic fungi was demonstrated.Conclusions:It can be concluded that the new ellagitannin(860.7 g/mol)isolated from E.antisyphilitica Zucc is an effective antifungal agent against Alternaria alternata,Fusarium oxyzporum,Colletotrichum gloeosporoides and Rhizoctnia solani.

  8. Econazole imprinted textiles with antifungal activity.

    Science.gov (United States)

    Hossain, Mirza Akram; Lalloz, Augustine; Benhaddou, Aicha; Pagniez, Fabrice; Raymond, Martine; Le Pape, Patrice; Simard, Pierre; Théberge, Karine; Leblond, Jeanne

    2016-04-01

    In this work, we propose pharmaceutical textiles imprinted with lipid microparticles of Econazole nitrate (ECN) as a mean to improve patient compliance while maintaining drug activity. Lipid microparticles were prepared and characterized by laser diffraction (3.5±0.1 μm). Using an optimized screen-printing method, microparticles were deposited on textiles, as observed by scanning electron microscopy. The drug content of textiles (97±3 μg/cm(2)) was reproducible and stable up to 4 months storage at 25 °C/65% Relative Humidity. Imprinted textiles exhibited a thermosensitive behavior, as witnessed by a fusion temperature of 34.8 °C, which enabled a larger drug release at 32 °C (temperature of the skin) than at room temperature. In vitro antifungal activity of ECN textiles was compared to commercial 1% (wt/wt) ECN cream Pevaryl®. ECN textiles maintained their antifungal activity against a broad range of Candida species as well as major dermatophyte species. In vivo, ECN textiles also preserved the antifungal efficacy of ECN on cutaneous candidiasis infection in mice. Ex vivo percutaneous absorption studies demonstrated that ECN released from pharmaceutical textiles concentrated more in the upper skin layers, where the fungal infections develop, as compared to dermal absorption of Pevaryl®. Overall, these results showed that this technology is promising to develop pharmaceutical garments textiles for the treatment of superficial fungal infections.

  9. Antifungal ellagitannin isolated from Euphorbia antisyphilitica Zucc

    Institute of Scientific and Technical Information of China (English)

    Juan Ascacio-Valds; Edgardo Burboa; Antonio F Aguilera-Carbo; Mario Aparicio; Ramn Prez-Schmidt; Ral Rodrguez; Cristbal N Aguilar

    2013-01-01

    Objective: To study antifungal activity of a new ellagitannin isolated from the plant residues of Euphorbia antisyphilitica (E. antisyphilitica) Zucc in the wax extraction process. Methods:An extract was prepared from dehydrated and pulverized residues and fractionated by liquid chromatography on Amberilte XAD-16, until obtained an ellagitannin-rich ethanolic fraction which was treated by rotaevaporation to recover the ellagitannin as fine powder. An aqueous solution was prepared and treated through ionic exchange liquid chromatography (Q XL) and gel permeation chromatography (G 25). The ellagitannin-rich fraction was thermogravimetrically evaluated (TGA and DTA) to test the thermo-stability of ellagic acid (monomeric unit). Then ellagitannin powder was analyzed by infrared spectrospcopy to determinate the functional groups and, also mass spectroscopy was used to determine the molecular ion. Results: The principal functional groups of ellagitannin were determined, the molecular weight was 860.7 g/mol; and an effective antifungal activity against phytopathogenic fungi was demonstrated. Conclusions: It can be concluded that the new ellagitannin (860.7 g/mol) isolated from E. antisyphilitica Zucc is an effective antifungal agent against Alternaria alternata, Fusarium oxyzporum, Colletotrichum gloeosporoides and Rhizoctnia solani.

  10. Strategies to manage antifungal drug resistance.

    Science.gov (United States)

    Tseng, Hsiang-Kuang; Perfect, John R

    2011-02-01

    Invasive fungal infections continue to cause significant morbidity and mortality in immunocompromised hosts. From more than half a million deaths from cryptococcosis in sub-Saharan Africa to an unchanging death rate from invasive candidiasis, despite three antifungal classes of drugs, insights into better strategies to reduce therapeutic failures or resistance are needed. This review examines the issues around antifungal drug resistance from both a basic description of the failures and how they are detected to the variety of issues that need to be addressed to help prevent failures for successful management. The reader will gain an understanding of the clinical complexities in this patient population for management of invasive fungal infections. Throughout the review, principles of management are given along with some specific clinical examples to illustrate the issues and frame the knowledge base. From this discussion it is hoped that the clinician can use the insights provided to manage individual patients and find links to the evidence-based material that support its conclusions. Also, this review specifically identifies the limitations of present management and directs clinicians to gather additional information and provide even better treatment strategies. Invasive fungal infections are life-threatening complications of serious underlying diseases. Their management can be complicated by both direct and clinical drug resistance and by understanding these possibilities and correcting them; most patients can be successfully managed with present antifungal drugs if the underlying diseases can be controlled.

  11. Nitrogen Isotopic Composition of Proteinaceous Coral Skeletal Amino Acids Records Change in Source Nitrate to the Euphotic Zone in the Western Tropical Pacific

    Science.gov (United States)

    Williams, B.; Thibodeau, B.; Chikaraishi, Y.; Ohkouchi, N.; Grottoli, A. G.

    2014-12-01

    Instrumental and proxy data and global climate model experiments indicate a multi-decadal shoaling of the western tropical Pacific (WTP) thermocline potentially related to a shift in ENSO frequency. In the WTP, the nutricline coincides with the thermocline, and a shoaling of the nutricline brings more nitrate-rich seawater higher in the water column and within the sunlit euphotic zone. In the nutrient-poor WTP, this incursion of nitrate-rich water at the bottom of the euphotic zone may stimulate productivity in the water column. However, there is a general paucity of measurements below the surface with which to investigate recent changes in seawater chemistry. Nitrogen isotope (δ15N) measurements of particulate organic matter (POM) can elucidate the source of nitrogen to the WTP and related trophic dynamics. This POM is the food source to the long-lived proteinaceous corals, and drives the nitrogen isotopic composition of their skeleton. Here, we report time series δ15N values from the banded skeletons of proteinaceous corals from offshore Palau in the WTP that provide proxy information about past changes in euphotic zone nitrogen dynamics. Bulk skeletal δ15N values declined between 1977 and 2010 suggesting a progressively increasing contribution of deep water with isotopically-light nitrate to the euphotic zone and/or a shortening of the planktonic food web. Since only some amino acids are enriched in δ15N with each trophic transfer in a food web, we measured the δ15N composition of seven individual amino acids in the same coral skeleton. The δ15N time series of the individual amino acids also declined over time, mirroring the bulk values. These new data indicate that the changes in the source nitrogen to the base of the euphotic zone drives a decline in coral skeletal δ15N values, consistent with the shoaling nutricline, with no coinciding alteration of the trophic structure in the WTP.

  12. Co-cultivation of antifungal Lactobacillus plantarum MiLAB 393 and Aspergillus nidulans, evaluation of effects on fungal growth and protein expression.

    Science.gov (United States)

    Ström, Katrin; Schnürer, Johan; Melin, Petter

    2005-05-01

    The fungal inhibitory effects of strain Lactobacillus plantarum MiLAB 393, producing broad-spectrum antifungal compounds, were evaluated. A co-cultivation method was set up to monitor effects on fungal growth and protein expression of growing Aspergillus nidulans with L. plantarum MiLAB 393. The effects of inhibitory metabolites produced by L. plantarum MiLAB 393, cyclo(l-Phe-l-Pro), lactic acid and 3-phenyllactic acid, were also investigated by addition of pure compounds to the growth medium of A. nidulans. The co-cultivation strongly affected the morphology of the fungal mycelium and decreased the biomass to 36% of control. Co-cultivation with Lactobacillus coryniformis MiLAB 123 gave only marginal morphological changes and minor biomass reduction, suggesting specific effects of L. plantarum MiLAB 393. The amount of several A. nidulans-proteins was increased during co-cultivation and by all of the inhibiting substances. This study shows that the growth of A. nidulans is inhibited during co-cultivation with L. plantarum MiLAB 393 and that the expression of fungal proteins is altered.

  13. Antifungal activity of some coleus species growing in nilgiris.

    Science.gov (United States)

    Nilani, P; Duraisamy, B; Dhanabal, P S; Khan, Saleemullah; Suresh, B; Shankar, V; Kavitha, K Y; Syamala, G

    2006-07-01

    The in vitro antifungal activity of solvent extracts of Coleus forskohlii, Coleus blumei and Coleus barbatus were compared by testing against some pathogenic fungi like Aspergillus niger, Aspergillusfumigatus, Aspergillus ruantii, Proteus vulgaris and Candida albicans. The petroleum ether extract of Coleus forskohlii and Coleus barbatus exhibited significant antifungal activity against all the selected organisms. The extracts of Coleus blumei did not show any significant antifungal activity against the selected organisms.

  14. Design, synthesis and antifungal activity of novel triazole derivatives

    Institute of Scientific and Technical Information of China (English)

    Qing lie Zhao; Yan Song; Hong Gang Hu; Shi Chong Yu; Qiu Ye Wu

    2007-01-01

    Twenty-three 1 -(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-(N-cycloproyl-N-substituted-amino)-2-propanols were designed and synthesized on the basis of the active site of lanosterol 14α-demethylase.In vitro antifungal activities showed that some of the title compounds had higher antifungal activity and broader antifungal spectrum than fluconazole.

  15. ANTIFUNGAL ACTIVITY OF SOME COLEUS SPECIES GROWING IN NILGIRIS

    OpenAIRE

    Nilani, P.; Duraisamy, B.; Dhanabal, P.S.; khan, Saleemullah; Suresh, B.; Shankar, V.; Kavitha, K.Y.; Syamala, G.

    2006-01-01

    The in vitro antifungal activity of solvent extracts of Coleus forskohlii, Coleus blumei and Coleus barbatus were compared by testing against some pathogenic fungi like Aspergillus niger, Aspergillus fumigatus, Aspergillus ruantii, Proteus vulgaris and Candida albicans. The petroleum ether extract of Coleus forskohlii and Coleus barbatus exhibited significant antifungal activity against all the selected organisms. The extracts of Coleus blumei did not show any significant antifungal activity ...

  16. 泊沙康唑体内及体外活性研究进展%In-vitro and in-vivo antifungal activities of posaconazole:an update

    Institute of Scientific and Technical Information of China (English)

    孙禾; 苏欣; 施毅

    2011-01-01

    泊沙康唑是广谱三唑类抗真菌新药,对大多数酵母菌和丝状真菌体外高度敏感,如念珠菌属、新型隐球菌、曲霉属、镰刀霉属及接合菌属等.对部分双相型真菌和地方性真菌,泊沙康唑也具有体外活性.对免疫正常及免疫抑制动物的侵袭性感染,泊沙康唑都有广谱、高效的抗真菌活性.对光滑念珠菌、克柔念珠菌、土曲霉、镰刀霉及接合菌等,泊沙康唑的体内外活性优于其他唑类药物.在体内敏感度研究中,对不同免疫状态及不同部位的重度侵袭性感染,泊沙康唑预防和治疗用药都显示了良好的效果.%Posaconazole is a new triazole drug with broad-spectrum activity in vitro against most yeasts and molds such as candidae, cryptococcus neoformans, aspergillus, Fusarium and zygomycetes, and also against certain species of dimorphic fungi and endemic fungi. In immunocompetent or immunocompromised animal models of invasive fungal infections, Posaconazole has been demonstrated to provide highly-effective, broad-spectrum antifungal activities. In-vitro and in-vivo activities of posaconazole were superior to those of other azoles against Candida gla-brata,Candida krusei, Aspergillus terms, fusarium and zygomycetes. In vivo sensitivity studies have shown the promising efficacy of posaconazole against life-threatening fungal infections in animal models with different immune status and sites of infections.

  17. Antifungal Poly(lactic acid Films Containing Thymol and Carvone

    Directory of Open Access Journals (Sweden)

    Boonruang Kanchana

    2016-01-01

    Full Text Available The goal of this study was to develop antifungal poly(lactic acid films for food packaging applications. The antifungal compounds, thymol and R-(--carvone were incorporated into poly(lactic acid (PLA-based polymer at 10, 15 and 20% by weight. Film converting process consists of three steps including melt blending, sheet extrusion and biaxial stretching. The incorporation of antifungal compounds into the polymer matrix resulted in decreased Tg and Tm, increased gas permeabilility, reduced tensile strength and increased elongation at break of the antifungal PLA films.

  18. Pathogenesis-related gene, JcPR-10a from Jatropha curcas exhibit RNase and antifungal activity.

    Science.gov (United States)

    Agarwal, Parinita; Bhatt, Vacha; Singh, Rekha; Das, Mamali; Sopory, Sudhir K; Chikara, Jitendra

    2013-06-01

    The pathogenesis-related proteins have a broad spectrum of roles, ranging from seed germination, development to resistance. The PR-10 is a multigene family differing from other PR proteins in being intracellular, small and acidic with similar 3D structures. We have isolated JcPR-10a cDNA with an ORF of 483 bp from J. curcas, an important biofuel crop grown in the wastelands of India. JcPR-10a gets clustered with dicots in phylogenetic tree. The genomic organisation analysis of JcPR-10a revealed the presence of an intron at conserved 185 bp position. Transcript expression of JcPR-10a was upregulated in response to different stimuli such as NaCl, salicylic acid, methyl jasmonate and M. phaseolina. In response to SA and Macrophomina the transcript was found increased at 48 h, however, in case of NaCl and MeJa a strong induction was observed at 12 h which decreased at 48 h. We first time report the transcript up regulation of PR-10 gene by Macrophomina, a pathogen causing collar rot in Jatropha. The recombinant E. coli cells showed better growth in LB medium supplemented with NaCl, whereas growth of recombinant cells was inhibited in LB medium supplemented with KCl, mannitol, sorbitol, methyl jasmonate and salicylic acid. The JcPR-10a protein was overexpressed in E. coli cells, and was purified to homogeneity, the purified protein exhibited RNase and DNase activity. Furthermore, the protein also showed antifungal activity against Macrophomina, indicating that JcPR-10a can serve as an important candidate to engineer stress tolerance in Jatropha as well as other plants susceptible to collar rot by Macrophomina.

  19. Clinicomycological Profile and Antifungal Sensitivity Pattern of Commonly Used Azoles in Dermatophytosis

    Directory of Open Access Journals (Sweden)

    Mahesh Mathur

    2015-06-01

    Conclusions: This study highlighted the increasing resistance of the antifungals, which is responsible for the treatment failure in dermatophye infections. Keywords: antifungal resistance; dermatophyte; epidemiology.

  20. Screening of Broad-spectrum Bacteriocin-producing Lactic Acid Bacteria Strain and Characteristics of Antibacterial Compounds%1株产广谱细菌素乳酸菌的筛选及其抑菌物质的特性

    Institute of Scientific and Technical Information of China (English)

    曹珂珂; 王娣; 李妍

    2012-01-01

    By A broad spectrum bacteriocin producing strain was screened by plant punching and its antibacterial characteristics was studied. The results showed that one baeteriocin-producing Lactic acid bacteria strain isolated from plant materials exhibited strong inhibition activity against the E. coil. The supernatant of this strain could still inhibit the growth of indicator strain strongly after eliminating hydrogen peroxide and organic acid. After treatment with pep- sin, the strain' s inhibitory activity decreased sharply, which showed the inhibitory substance possessed the character- istic of protein, and it could be named bacterioein. The strain was identified as Laetobacillus plantarum through detec- tion of its appearance, physiological and biochemical characteristics. The inhibitory activity of strain fermentation su- pernatant was not affected by high temperature, 1% Tween-80, SDS, EDTA and the low pH. However, its inhibitory activity revealed an obvious decrease after treatment with protease K and trypsin than with pepsin. The bacterial inhi- bition spectrum showed that this was a kind of bacteriocin with wide inhibition soectrum.%从植物性材料中筛选到1株对大肠杆菌有明显抑制作用的乳酸菌,在排除有机酸和过氧化氢的干扰后,该菌株的发酵上清液仍有较强的抑菌性;胃蛋白酶处理后,抑菌活性明显降低,说明其抑菌物质为蛋白质类物质,是一种细菌素。通过形态学和生理生化分析,初步鉴定该菌株为植物乳杆菌。生物学特性研究表明,该菌株发酵上清液经高温、吐温-80、SDS、EDTA处理后,仍保持较好的抑菌活性;在酸性条件下稳定;对蛋白酶K和胰蛋白酶较胃蛋白酶敏感。抑菌谱显示,该菌株的发酵上清液具有广谱抑菌性。

  1. Optimization of Antifungal Extracts from Ficus hirta Fruits Using Response Surface Methodology and Antifungal Activity Tests

    Directory of Open Access Journals (Sweden)

    Chuying Chen

    2015-10-01

    Full Text Available The fruits of Ficus hirta (FH display strong antifungal activity against Penicillium italicum and Penicillium digitatum. In order to optimize the extraction conditions of antifungal extracts from FH fruit, various extraction parameters, such as ethanol concentration, extraction time, solvent to solid ratio and temperature, were chosen to identify their effects on the diameters of inhibition zones (DIZs against these two Penicillium molds. Response surface methodology (RSM was applied to obtain the optimal combination of these parameters. Results showed that the optimal extraction parameters for maximum antifungal activity were: 90% (v/v ethanol concentration, 65 min extraction time, 31 mL/g solvent to solid ratio and 51 °C temperature. Under the abovementioned extraction conditions, the experimental DIZs values obtained experimentally were 57.17 ± 0.75 and 39.33 ± 0.82 mm, which were very close to the values of 57.26 and 39.29 mm predicted by the model. Further, nine kinds of phytopathogens were tested in vitro to explore the antifungal activity of the FH extracts. It was found for the first time that the FH extracts showed significant inhibition on the growth of P. italicum, A. citri, P. vexans, P. cytosporella and P. digitatum.

  2. Antifungal and antiviral products of marine organisms.

    Science.gov (United States)

    Cheung, Randy Chi Fai; Wong, Jack Ho; Pan, Wen Liang; Chan, Yau Sang; Yin, Cui Ming; Dan, Xiu Li; Wang, He Xiang; Fang, Evandro Fei; Lam, Sze Kwan; Ngai, Patrick Hung Kui; Xia, Li Xin; Liu, Fang; Ye, Xiu Yun; Zhang, Guo Qing; Liu, Qing Hong; Sha, Ou; Lin, Peng; Ki, Chan; Bekhit, Adnan A; Bekhit, Alaa El-Din; Wan, David Chi Cheong; Ye, Xiu Juan; Xia, Jiang; Ng, Tzi Bun

    2014-04-01

    Marine organisms including bacteria, fungi, algae, sponges, echinoderms, mollusks, and cephalochordates produce a variety of products with antifungal activity including bacterial chitinases, lipopeptides, and lactones; fungal (-)-sclerotiorin and peptaibols, purpurides B and C, berkedrimane B and purpuride; algal gambieric acids A and B, phlorotannins; 3,5-dibromo-2-(3,5-dibromo-2-methoxyphenoxy)phenol, spongistatin 1, eurysterols A and B, nortetillapyrone, bromotyrosine alkaloids, bis-indole alkaloid, ageloxime B and (-)-ageloxime D, haliscosamine, hamigeran G, hippolachnin A from sponges; echinoderm triterpene glycosides and alkene sulfates; molluscan kahalalide F and a 1485-Da peptide with a sequence SRSELIVHQR; and cepalochordate chitotriosidase and a 5026.9-Da antifungal peptide. The antiviral compounds from marine organisms include bacterial polysaccharide and furan-2-yl acetate; fungal macrolide, purpurester A, purpurquinone B, isoindolone derivatives, alterporriol Q, tetrahydroaltersolanol C and asperterrestide A, algal diterpenes, xylogalactofucan, alginic acid, glycolipid sulfoquinovosyldiacylglycerol, sulfated polysaccharide p-KG03, meroditerpenoids, methyl ester derivative of vatomaric acid, lectins, polysaccharides, tannins, cnidarian zoanthoxanthin alkaloids, norditerpenoid and capilloquinol; crustacean antilipopolysaccharide factors, molluscan hemocyanin; echinoderm triterpenoid glycosides; tunicate didemnin B, tamandarins A and B and; tilapia hepcidin 1-5 (TH 1-5), seabream SauMx1, SauMx2, and SauMx3, and orange-spotted grouper β-defensin. Although the mechanisms of antifungal and antiviral activities of only some of the aforementioned compounds have been elucidated, the possibility to use those known to have distinctly different mechanisms, good bioavailability, and minimal toxicity in combination therapy remains to be investigated. It is also worthwhile to test the marine antimicrobials for possible synergism with existing drugs. The prospects of

  3. Synthesis of Novel Antifungal Triazole Compounds

    Institute of Scientific and Technical Information of China (English)

    Yong CHU; Ming Xia XU; Ding LU

    2004-01-01

    Based on our previous studies of 3D-QSAR, 38 novel objective compounds belonging to 4 series were designed and successfully synthesized directed by the idea of reconstructing the structure of non-pharmacophores while reserving essential ones in triazoles. In vitro pilot studies on their antifungal activities showed that most compounds have inhibitory effects on C.albicans and some inhibit S.cerevisiae also. The effects on C.albicans of 5 compounds are more potent than or equal to that of fluconazole or itraconazole.

  4. Nylon-3 polymers with selective antifungal activity.

    Science.gov (United States)

    Liu, Runhui; Chen, Xinyu; Hayouka, Zvi; Chakraborty, Saswata; Falk, Shaun P; Weisblum, Bernard; Masters, Kristyn S; Gellman, Samuel H

    2013-04-10

    Host-defense peptides inhibit bacterial growth but show little toxicity toward mammalian cells. A variety of synthetic polymers have been reported to mimic this antibacterial selectivity; however, achieving comparable selectivity for fungi is more difficult because these pathogens are eukaryotes. Here we report nylon-3 polymers based on a novel subunit that display potent antifungal activity (MIC = 3.1 μg/mL for Candida albicans ) and favorable selectivity (IC10 > 400 μg/mL for 3T3 fibroblast toxicity; HC10 > 400 μg/mL for hemolysis).

  5. Chemical modification of antifungal polyene macrolide antibiotics

    Science.gov (United States)

    Solovieva, S. E.; Olsufyeva, E. N.; Preobrazhenskaya, M. N.

    2011-02-01

    The review summarizes advances in the methods for the synthesis of polyene antibiotics (amphotericin B, partricin A, etc.) and investigations of the structure-activity relationship made in the last 15 years. State-of-the-art approaches based on the combination of the chemical synthesis and genetic engineering are considered. Emphasis is given to the design of semisynthetic antifungal agents against chemotherapy-resistant pathogens having the highest therapeutic indices. Recent results of research on the mechanisms of action of polyenes are outlined.

  6. Chemical modification of antifungal polyene macrolide antibiotics

    Energy Technology Data Exchange (ETDEWEB)

    Solovieva, S E; Olsufyeva, E N; Preobrazhenskaya, M N [G.F.Gause Institute of New Antibiotics, Russian Academy of Medical Sciences (Russian Federation)

    2011-02-28

    The review summarizes advances in the methods for the synthesis of polyene antibiotics (amphotericin B, partricin A, etc.) and investigations of the structure-activity relationship made in the last 15 years. State-of-the-art approaches based on the combination of the chemical synthesis and genetic engineering are considered. Emphasis is given to the design of semisynthetic antifungal agents against chemotherapy-resistant pathogens having the highest therapeutic indices. Recent results of research on the mechanisms of action of polyenes are outlined.

  7. Progress in antibacterial and antifungal chemotherapy.

    Science.gov (United States)

    Fromtling, R A

    2000-08-01

    The European Society of Clinical Microbiology and Infectious Diseases sponsored the 10th European Congress on Clinical Microbiology and Infectious Diseases in Stockholm, Sweden, May 28-31, 2000. At the ECMID, well-attended sessions were held which focused on the pathogenesis and therapy of viral, bacterial and fungal diseases. This report focuses on new information on resistance to antibacterial agents, including data from recent surveillance studies, and the in vitro and investigational clinical activity of new antibacterial (moxifloxacin, telithromycin) and antifungal (fluconazole, itraconazole, voriconazole, amphotericin B, liposomal formulations of amphotericin B, terbinafine and the candins) drugs.

  8. Nosocomial Candidiasis: Antifungal Stewardship and the Importance of Rapid Diagnosis.

    Science.gov (United States)

    Pfaller, Michael A; Castanheira, Mariana

    2016-01-01

    Candidemia and other forms of candidiasis are associated with considerable excess mortality and costs. Despite the addition of several new antifungal agents with improved spectrum and potency, the frequency of Candida infection and associated mortality have not decreased in the past two decades. The lack of rapid and sensitive diagnostic tests has led to considerable overuse of antifungal agents resulting in increased costs, selection pressure for resistance, unnecessary drug toxicity, and adverse drug interactions. Both the lack of timely diagnostic tests and emergence of antifungal resistance pose considerable problems for antifungal stewardship. Whereas antifungal stewardship with a focus on nosocomial candidiasis should be able to improve the administration of antifungal therapy in terms of drug selection, proper dose and duration, source control and de-escalation therapy, an important parameter, timeliness of antifungal therapy, remains a victim of slow and insensitive diagnostic tests. Fortunately, new proteomic and molecular diagnostic tools are improving the time to species identification and detection. In this review we will describe the potential impact that rapid diagnostic testing and antifungal stewardship can have on the management of nosocomial candidiasis.

  9. Antifungal cyclic peptides from the marine sponge Microscleroderma herdmani

    Science.gov (United States)

    Screening natural product extracts from National Cancer Institute Open Repository for antifungal discovery afforded hits for bioassay-guided fractionation. Upon LC-MS analysis of column fractions with antifungal activities to generate information on chemical structure, two new cyclic hexapeptides, m...

  10. Antifungal and antioxidant activities of the phytomedicine pipsissewa, Chimaphila umbellata.

    NARCIS (Netherlands)

    Galván, I.; Mir-Rashed, N.; Jessulat, M.; Atanya, M.; Golshani, A.; Boekhout, T.; Durst, T.; Petit, P.; Amiguet, V.T.; Summerbell, R.C.; Cruz, I.; Arnason, J.T.; Smith, M.L.

    2008-01-01

    Bioassay-guided fractionation of Chimaphila umbellata (L.) W. Bart (Pyrolaceae) ethanol extracts led to the identification of 2,7-dimethyl-1,4-naphthoquinone (chimaphilin) as the principal antifungal component. The structure of chimaphilin was confirmed by 1H and 13C NMR spectroscopy. The antifungal

  11. Cuticular antifungals in spiders: density- and condition dependence.

    Science.gov (United States)

    González-Tokman, Daniel; Ruch, Jasmin; Pulpitel, Tamara; Ponton, Fleur

    2014-01-01

    Animals living in groups face a high risk of disease contagion. In many arthropod species, cuticular antimicrobials constitute the first protective barrier that prevents infections. Here we report that group-living spiders produce cuticular chemicals which inhibit fungal growth. Given that cuticular antifungals may be costly to produce, we explored whether they can be modulated according to the risk of contagion (i.e. under high densities). For this purpose, we quantified cuticular antifungal activity in the subsocial crab spider Diaea ergandros in both natural nests and experimentally manipulated nests of varying density. We quantified the body-condition of spiders to test whether antifungal activity is condition dependent, as well as the effect of spider density on body-condition. We predicted cuticular antifungal activity to increase and body-condition to decrease with high spider densities, and that antifungal activity would be inversely related to body-condition. Contrary to our predictions, antifungal activity was neither density- nor condition-dependent. However, body-condition decreased with density in natural nests, but increased in experimental nests. We suggest that pathogen pressure is so important in nature that it maintains high levels of cuticular antifungal activity in spiders, impacting negatively on individual energetic condition. Future studies should identify the chemical structure of the isolated antifungal compounds in order to understand the physiological basis of a trade-off between disease prevention and energetic condition caused by group living, and its consequences in the evolution of sociality in spiders.

  12. Antifungal activity of Piper diospyrifolium Kunth (Piperaceae) essential oil

    Science.gov (United States)

    Vieira, Silvia Cristina Heredia; de Paulo, Luis Fernando; Svidzinski, Terezinha Inez Estivaleti; Dias Filho, Benedito Prado; Nakamura, Celso Vataru; de Souza, Amanda; Young, Maria Cláudia Marx; Cortez, Diógenes Aparício Garcia

    2011-01-01

    In vitro activity of the essential oil from Piper diospyrifolium leaves was tested using disk diffusion techniques. The antifungal assay showed significant potencial antifungal activity: the oil was effective against several clinical fungal strains. The majority compounds in the essential oil were identified as sesquiterpenoids by GC-MS and GC-FID techniques. PMID:24031717

  13. DYSREGULATION OF ION HOMEOSTASIS BY ANTIFUNGAL AGENTS

    Directory of Open Access Journals (Sweden)

    Yongqiang eZhang

    2012-04-01

    Full Text Available Ion signaling and transduction networks are central to fungal development and virulence because they regulate gene expression, filamentation, host association and invasion, pathogen stress response and survival. Dysregulation of ion homeostasis rapidly mediates cell death, forming the mechanistic basis by which a growing number of amphipathic but structurally unrelated compounds elicit antifungal activity. Included in this group is carvacrol, a terpenoid phenol that is a prominent component of oregano and other plant essential oils. Carvacrol triggers an early dose dependent Ca2+ burst and long lasting pH changes in the model yeast S. cerevisiae. The distinct phases of ionic transients and a robust transcriptional response that overlaps with Ca2+ stress and nutrient starvation point to specific signaling events elicited by plant terpenoid phenols, rather than a non-specific lesion of the membrane as was previously considered. We discuss the potential use of plant essential oils and other agents that disrupt ion signaling pathways as chemosensitizers to augment conventional antifungal therapy, and to convert fungistatic drugs with strong safety profiles into fungicides.

  14. Selective sweeps in Cryptocercus woodroach antifungal proteins.

    Science.gov (United States)

    Velenovsky, Joseph F; Kalisch, Jessica; Bulmer, Mark S

    2016-10-01

    We identified the antifungal gene termicin in three species of Cryptocercus woodroaches. Cryptocercus represents the closest living cockroach lineage of termites, which suggests that the antifungal role of termicin evolved prior to the divergence of termites from other cockroaches. An analysis of Cryptocercus termicin and two β-1,3-glucanase genes (GNBP1 and GNBP2), which appear to work synergistically with termicin in termites, revealed evidence of selection in these proteins. We identified the signature of past selective sweeps within GNBP2 from Cryptocercus punctulatus and Cryptocercus wrighti. The signature of past selective sweeps was also found within termicin from Cryptocercus punctulatus and Cryptocercus darwini. Our analysis further suggests a phenotypically identical variant of GNBP2 was maintained within Cryptocercus punctulatus, Cryptocercus wrighti, and Cryptocercus darwini while synonymous sites diverged. Cryptocercus termicin and GNBP2 appear to have experienced similar selective pressure to that of their termite orthologues in Reticulitermes. This selective pressure may be a result of ubiquitous entomopathogenic fungal pathogens such as Metarhizium. This study further reveals the similarities between Cryptocercus woodroaches and termites.

  15. Research Antifungal Activity on Bacteriocin Produced by Lactic Acid Bacteria from Traditional Sour Cabbage%传统酸菜中具有抗真菌特性乳酸菌素的研究

    Institute of Scientific and Technical Information of China (English)

    李传娟; 双全; 栗永乐; 萨如拉; 桑木信辅; 琢田爱

    2012-01-01

    The antibacterial ability of lactic acid bacteria (LAB), which isolated from the sour cabbage juice prepared by herdsman in the east Inner Mogolia Region, were determined by Plate punch diffusion method, and the extracellulary bacteriocins of one screening strain was partial purified by gel filtration Sephadex G-15, and its biochemical characteristics were assessed in vitro. The results showed that strain S1-4 of LAB, which was screened out from 84 tested strains, had a broad spectrum antibacterial fungi property. Purified extracellulary bacteriocins from strain S1-4 was characterised as a proteinaceous substance. This bacteriocins compound, molecular mass ranged from 6.5 kDa to 8 kDa, has thermal stability and acid tolerance with an optimum antibacterial ability at pH 4.0.%通过平板打孔扩散法测定从内蒙古东部地区传统酸菜汁中分离的乳酸菌(LAB)的抑菌能力,再用葡聚糖凝胶G-15对筛选乳酸菌的胞外细菌素进行分离及特性研究。结果显示,84株供试乳酸菌中筛选出1株具有广谱抗真菌能力的乳酸菌S1-4。该乳酸菌所产生的胞外抑菌素属蛋白类物质,具有热稳定和耐酸特性,在pH4.0时抑菌效果最佳,其分子量约为6.5KDa~8kDa。

  16. 土壤放线菌K2的筛选、鉴定及其抑菌活性初探%The Study on Antifungal Activity, Screening and Identification of Actinomycete K2 Strain from Soil

    Institute of Scientific and Technical Information of China (English)

    赵丽坤; 田永强; 高磊; 孙盈

    2013-01-01

      筛选具有抑制植物病原菌活性的放线菌是农用抗生素开发的基础。通过平板对峙法筛选出8株拮抗放线菌菌株,采用生长速率法测定获得一株对植物病原菌有较好抑菌作用的菌株K2,并采用抑制菌丝生长速率法对其抑菌谱进行研究,以及进行菌种鉴定。生长速率法试验表明,放线菌菌株K2发酵液对10种供试植物病原菌菌丝生长均有不同程度的抑制作用,其中以对尖孢镰刀菌(Fusarium oxysporum)抑制效果最好,抑菌率可达57.38%。根据形态学特征、生理生化特征和基于16S rDNA序列比对,鉴定菌株 K2属于链霉菌属(Streptomyces)的一个菌株。放线菌 K2的代谢产物具有较广的抑菌谱,对植物病原菌的防治有很大的研究开发潜力。%Screening antifungal actinomycetes were the foundation of agricultural antibiotics exploitation. The antifungal activity of 8 strains actinomycetes were studied by flat confrontation, one strain named K2 was got by mycelim growth rate, its antimicrobial spectrum was studied and strains identification with mycelim growth rate. The result of mycelium growth rate showed that K2 had a broad spectrum inhibitory activity to all the tested 10 plant pathogenic fungi. Among these, activity against Fusarium oxysporum was the highest with inhibition rate of 57.38%. The results based on morphological characteristics, physiological and biochemical characterization and 16S rDNA sequence analysis of strain K2 showed that it was possibly Streptomyces. The K2 strain displayed a broad spectrum inhibitory activity, which had great potential for controlling plant pathogens.

  17. The peculiar structural features of kiwi fruit pectin methylesterase: amino acid sequence, oligosaccharides structure, and modeling of the interaction with its natural proteinaceous inhibitor.

    Science.gov (United States)

    Ciardiello, M Antonietta; D'Avino, Rossana; Amoresano, Angela; Tuppo, Lisa; Carpentieri, Andrea; Carratore, Vito; Tamburrini, Maurizio; Giovane, Alfonso; Pucci, Piero; Camardella, Laura

    2008-04-01

    Pectin methylesterase (PME) from kiwi fruit (Actinidia deliciosa) is a glycoprotein, showing an apparent molecular mass of 50 kDa upon size exclusion chromatography and SDS-PAGE. The primary structure, elucidated by direct sequencing of the protein, comprises 321 amino acid residues providing a molecular mass of 35 kDa. The protein has an acetylated Thr residue at the amino terminus and five N-glycosylation consensus sequences, four of which are actually glycosylated. A careful investigation of the oligosaccharide structures demonstrated that PME glycans belong to complex type oligosaccharides essentially consisting of xylosylated polyfucosylated biantennary structures. Alignment with known mature plant PME sequences indicates that the postulated active site residues are conserved. Kiwi PME activity is inhibited following the interaction with the proteinaceous inhibitor PMEI, isolated from the same source. Gel-filtration experiments show that kiwi PME/PMEI complex is stable in a large pH range and dissociates only at pH 10.0. Modeling of the interaction with the inhibitor was performed by using the crystal structure of the complex between kiwi PMEI and tomato PME as a template. The model shows that the binding site is the same reported for tomato PME. However, additional salt link interactions are found to connect the external loops of kiwi PME to PMEI. This finding may explain the higher pH stability of the complex formed by the two kiwi proteins respect to that formed by PMEI and tomato PME.

  18. ISOLATION AND IDENTIFICATION OF ROT-CAUSING FUNGI OF WINTER JUJUBE IN STORAGE PERIOD AND SCREENING OF BROAD SPECTRUM ANTAGONIST%冬枣储藏期致腐真菌分离鉴定及广谱拮抗菌株的筛选

    Institute of Scientific and Technical Information of China (English)

    李静琴; 陈亮; 岳贵龙; 蔡静平

    2013-01-01

    Four rot-causing fungi were isolated from the rotten tissues of winter jujube and identified as Rhizomorpha Roth.ex FT, Alternaria tenuissima, Coniothyrium olivaceum and Penicillium expansum. 142 bacteria strains were isolated from different samples by dilution method, and 7 strains with remarkable antagonistic effect against the four rot-causing fungi were screened from the 142 bacteria strains by antagonistic cultivation method, strain LM2303 had the best broad spectrum antagonistic effect, and the inhibition zone widths of strain LM2303 to the four rot-causing fungi were respectively (8.5± 0.5) mm, (8.0± 0.3) mm, (10.3± 0.6) mm and (7.5± 0.9) mm. Based on morphologic observation, physiological-biochemical characteristic analysis and 16S rDNA sequence comparison, strain LM2303 should be Bacillus subtilis. Accordingly, strain LM2303 has significant antagonistic effect against the main rot-causing fungi of winter jujube, thereby laying the foundation for biocontrol of rot-causing fungi on winter jujube during storage.%从不同腐烂病症的冬枣中分离得到致腐真菌4株,经鉴定分别为根菌索菌(Rhizomorpha Roth.ex Fr)、细极链格孢(Alternaria tenuissima)、橄榄色盾壳霉(Coniothyrium olivaceum)、扩展青霉(Penicillium expansum);采用稀释分离法从样品中分离得到细菌菌株142株,采用对峙培养法从中筛选到对4种致腐真菌均具有明显拮抗作用的细菌菌株7株,其中菌株LM2303的广谱拮抗效果最佳,其对上述4种致腐真菌的抑菌带宽度分别为(8.5±0.5) mm、(8.0±0.3)mm、(10.3±0.6) mm和(7.5±0.9) mm;通过形态学观察、生理生化特性分析及16S rDNA序列比对,菌株LM2303应为枯草芽孢杆菌(Bacillus subtilis).菌株LM2303对冬枣主要致腐真菌均具有显著的拮抗作用,为冬枣储藏期致腐真菌生物防控奠定了基础.

  19. Preservative Effect of Broad-Spectrum Enterocin LM-2 on Cold Sliced Ham%广谱乳酸菌细菌素enterocin LM-2对低温切片火腿的防腐保鲜效果(英文)

    Institute of Scientific and Technical Information of China (English)

    刘国荣; 王成涛; 王洋; 张宝; 李平兰

    2012-01-01

    为考察广谱乳酸菌细菌素enterocin LM-2对低温切片火腿的防腐保鲜效果,并探讨其在低温肉制品防腐保鲜中的应用可行性。本研究在不添加任何化学防腐剂的前提下,分别添加80、320、1280AU/g enterocin LM-2处理低温切片火腿,分析不同浓度细菌素处理前后样品中微生物数量、理化指标以及感官特性的变化。结果发现:细菌素enterocin LM-2的添加可明显延长低温切片火腿的货架期,有效减少贮藏过程中挥发性盐基氮的生成及脂肪氧化程度,并保持产品原有色泽、气味、质构等感官特性。综合微生物和理化特性分析结果,确定添加1280AU/g enterocin LM-2的处理组防腐效果最好,可将低温切片火腿的货架期延长至49d。这些结果都显示出乳酸菌细菌素enterocin LM-2有作为天然生物防腐剂应用于低温肉制品防腐保鲜中的巨大应用潜力。%Enterocin LM-2,a broad-spectrum bacteriocin isolated from Chinese traditional cheese,was produced by Enterococcus faecium LM-2.In order to examine the potential of enterocin LM-2 as a biopreservative in sliced cooked ham,the effect of enterocin LM-2 at different concentrations(80,320,1280 AU/g) on microbiological,physicochemical and sensory quality properties of sliced cooked ham during the refrigerated storage at 4 ℃ was explored in this paper.The addition of enterocin LM-2 could substantially suppress the growth of microflora,especially Listeria monocytogenes and Salmonella enteritidis,and decrease the accumulation of TVB-N and lipid oxidation during refrigerated storage of sliced cooked ham.Overall,the most effective treatment was achieved by adding 1280 AU/g enterocin LM-2,which could extend the shelf life up to 49 days and produce a better sensory profile during the whole storage period.These results clearly indicate that enterocin LM-2 has a great potential as a biopreservative for enhancing the safety and quality of refrigerated sliced cooked

  20. 肺炎克雷伯菌中超广谱β-内酰胺酶基因分布及转移研究%The distribution and transfer of genes of duper broad-spectrumβ-lactamase in klebsiella pneumoniae

    Institute of Scientific and Technical Information of China (English)

    卢锋

    2014-01-01

    目的:研究肺炎克雷伯菌中超广谱β-内酰胺酶(ESBLs)基因类型及转移方式。方法回顾性分析该院2011年1月至2013年1月收集的460例住院患者菌株的临床资料,并对其ESBLs基因进行分型和研究耐药性。结果460株β-内酰胺酶的KPN检出6种β-内酰胺酶基因,其中bla TEM占总数的5%,bla SHV占总数的20%, bla CTX-M-1群占总数的5%,bla CTX-M-9群占总数的25%,bla OXA-1群占总数的10%,bla DHA 占总数的30%等;本研究共发现322种菌株耐药谱,菌株耐药在9种抗菌药物以上。阿莫西林/替卡西林/头孢噻吩等、阿莫西林/克拉维酸和头孢西丁、哌拉西林/克拉维酸、亚胺培南的耐药性分别为100%、60%、45%、35%和0。结论肺炎克雷伯菌中ESBLs基因类型主要是bla TEM和bla CTX-M-1,并具有较为严重的耐药性。%Objective To study the distribution and transfer of genes of super broad-spectrum β-lactamase (ESBL s) in klebsiella pneumoniae .Methods The information of 460 strains of hospitalized patients who had been treated in our hospital from January 2011 to January 2013 were retrospectively analyzed .Results 460 β-lactamase KPN detected six kinds of β-lactamase gene ,which bla TEM of the total 5% ,bla SHV accounted for 20% ,bla CTX-M-1 group accounted for 5% ,bla CTX-M-9 group accounted for 25% ,bla OXA-1 group accounted for 10% ,bla DHA 30% of the total ,etc .;this study found that 322 strains resistant spectrum ,strains resistant to antibiotics in 9 above .Amoxicillin/ticarcillin/cephalosporin thiophene ,amoxicillin/clavulanic acid ,cefoxitin ,piperacillin/clavulanic acid ,imipenem were 100% ,60% ,45% ,35% and 0 .Conclusion Klebsiella pneumoniae Super spectrum β-lactamase gene type are primarily bla TEM and bla CTX-M-1 ,they have more serious resistance .

  1. 炎症及炎症耐受模型筛选广谱趋化因子抑制肽%Screening for a Peptide That Inhibits Expression of a Broad-spectrum of Chemokines Using Models of Endotoxin Tolerance and LPS-induced Pro-inflammation

    Institute of Scientific and Technical Information of China (English)

    苏焱; 孙晗笑; 李秀英; 莫雪梅; 张光

    2013-01-01

    The goal of this study was to screen bioactive peptides to identify an efficient antagonist of multiple pro-inflammatory chemokines that inhibits the pathological process of inflammatory diseases.A phage display library was sequentially screened by binding phages.The binding properties of individual phage clones to LPS-activated PBMCs were determined using cell-based ELISAs.The positive clones were selected and determined by chemotaxis assays.A high-activity peptide was determined to inhibit carrageenan-induced paw oedema and formaldehyde-induced arthritis in Wistar rats in vivo.A possible mechanism of inflammation inhibition involving chemokine mRNA by the peptide was determined by analyzing mRNA expression levels of chemokines and tristetraprolin (TTP) by SqRT-PCR.Nineteen phage clones were selected after four rounds of biopanning with a cut-off of 3-fold higher binding to LPS-activated PBMCs than to normal PBMCs.Nine of the phage clones inhibited IL-8,MCP-1,and MIP-1 β production in vitro.Five clones displayed the same peptide(CI-S5)most robustly inhibited the chemotactic activity in vitro and reduced paw oedema and arthritis in Wistar rats in vivo.SqRT-PCR results indicated that mRNA expression of IL-8,MCP-1,and MIP-1 β were reduced and TTP mRNA expression was increased in the CI-S5 treatment group.Our data demonstrate that CI-S5 is a broad-spectrum antagonist of pro-inflammatory chemokines as it enhances the expression of TTP to reduce chemokine mRNA expression.This study provides a basis for the development of new peptide-based therapies for the treatment of inflammatory diseases.%通过减少炎性组织或细胞趋化因子及炎性因子的表达量能将炎症性病理过程抑制在起始阶段.我们通过体外构建人外周血单个核细胞LPS激活的急性炎症模型及内毒素耐受模型,进行噬菌体肽库亲和筛选,ELISA检测与炎性PBMC的结合能力,分泌抑制实验筛选抑制性噬菌体克隆,经趋化抑制、竞争结合

  2. Screening of Iranian plants for antifungal activity: Part 2

    Directory of Open Access Journals (Sweden)

    "Amin Gh.R

    2002-08-01

    Full Text Available In this study, 278 species from 37 families of native Iranian plants were screened for in vitro antifungal activity against 19 fungal strains. Initially, the crude extracts in concentration of 100 μg/ml were tested. Among 278 plant extracts, 201(71.27% of them showed antifungal activity against at least one fungal strain. A wide range of total extracts of different species were shown to have potentially noticeable antifungal effects. The outstanding species were: Mentha longifolia, Saliva multicaulis, Thymus transcaspicus, Zataria multiflora, Glycyrrhiza glabra, Hulthemia persica, Heracleum persicum, Pimpinella anisum, Pragnos ferulacea, Pragnos uloptera, and Viola odorata.

  3. Spectrophotometric reading of EUCAST antifungal susceptibility testing of Aspergillus fumigatus

    DEFF Research Database (Denmark)

    Meletiadis, J; Leth Mortensen, K; Verweij, P E

    2017-01-01

    OBJECTIVES: Given the increasing number of antifungal drugs and the emergence of resistant Aspergillus isolates, objective, automated and high-throughput antifungal susceptibility testing is important. The EUCAST E.Def 9.3 reference method for MIC determination of Aspergillus species relies...... on visual reading. Spectrophotometric reading was not adopted because of concern that non-uniform filamentous growth might lead to unreliable and non-reproducible results. We therefore evaluated spectrophotometric reading for the determination of MICs of antifungal azoles against Aspergillus fumigatus...... agreement of 90%-100% (Aspergillus species....

  4. Antifungal Treatment in Stem Cell Transplantation Centers in Turkey.

    Science.gov (United States)

    Akan, Hamdi; Atilla, Erden

    2016-03-05

    Despite the development of various guidelines, the approach to antifungal treatment in stem cell transplantation centers differs according to country or even between centers. This led to the development of another survey that aims to understand the antifungal treatment policies of Turkish stem cell transplantation centers. Although there has been an increasing trend towards the use of diagnostic-based treatments in Turkey in the last few years, empirical treatment is still the main approach. The practices of the stem cell transplantation centers reflect the general trends and controversies in this area, while there is a considerable use of antifungal combination therapy.

  5. Antifungal activity of a virally encoded gene in transgenic wheat.

    Science.gov (United States)

    Clausen, M; Kräuter, R; Schachermayr, G; Potrykus, I; Sautter, C

    2000-04-01

    The cDNA encoding the antifungal protein KP4 from Ustilago maydis-infecting virus was inserted behind the ubiquitin promoter of maize and genetically transferred to wheat varieties particularly susceptible to stinking smut (Tilletia tritici) disease. The transgene was integrated and inherited over several generations. Of seven transgenic lines, three showed antifungal activity against U. maydis. The antifungal activity correlated with the presence of the KP4 transgene. KP4-transgenic, soil-grown wheat plants exhibit increased endogenous resistance against stinking smut.

  6. Sarcoidosis Treatment with Antifungal Medication: A Follow-Up

    Directory of Open Access Journals (Sweden)

    Marjeta Terčelj

    2014-01-01

    Full Text Available Introduction. The aim of the study was to compare treatment of sarcoidosis with antifungal or corticosteroid medication. Methods. In patients with sarcoidosis antifungal medication (n=29, corticosteroids (n=21 or a combination (n=27 was given. Nine patients allotted to antifungal medication were later given corticosteroids because of the lack of regression of the disease. X-ray scores for the severity of granuloma infiltration were determined. Chitotriosidase and angiotensin converting enzyme were determined. The time in months till remission was observed as well as the number of recurrences.

  7. Can agricultural fungicides accelerate the discovery of human antifungal drugs?

    Science.gov (United States)

    Myung, Kyung; Klittich, Carla J R

    2015-01-01

    Twelve drugs from four chemical classes are currently available for treatment of systemic fungal infections in humans. By contrast, more than 100 structurally distinct compounds from over 30 chemical classes have been developed as agricultural fungicides, and these fungicides target many modes of action not represented among human antifungal drugs. In this article we introduce the diverse aspects of agricultural fungicides and compare them with human antifungal drugs. We propose that the information gained from the development of agricultural fungicides can be applied to the discovery of new mechanisms of action and new antifungal agents for the management of human fungal infections.

  8. An antifungal peptide from baby lima bean.

    Science.gov (United States)

    Wang, H X; Ng, T B

    2006-12-01

    A 6-kDa antifungal peptide with inhibitory activity on mycelial growth in Fusarium oxysporum, Mycosphaerella arachidicola, and Physalospora piricola was isolated from baby lima beans. The peptide suppressed growth in M. arachidicola with an IC(50) of 0.87 muM and inhibited activity of HIV-1 reverse transcriptase with an IC(50) of 4 muM. The peptide exhibited an N-terminal amino acid sequence similar to those of leguminous defensins. The isolation procedure comprised ion exchange chromatography on diethylaminoethyl (DEAE)-cellulose, affinity chromatography on Affi-gel blue gel, ion exchange chromatography on carboxymethyl (CM)-cellulose, and gel filtration by fast protein liquid chromatography on Superdex 75. The peptide was unadsorbed on DEAE-cellulose and Affi-gel blue gel but was adsorbed on CM-cellulose.

  9. Pomegranin, an antifungal peptide from pomegranate peels.

    Science.gov (United States)

    Guo, Guang; Wang, He Xiang; Ng, Tzi Bun

    2009-01-01

    A new antifungal peptide designated as pomegranin, with an N-terminal sequence resembling that of rice disease resistance NB-S-LRR-like protein, was isolated from fresh pomegranate peels by ion exchange chromatography on DEAE-cellulose, affinity chromatography on Affi-gel blue gel, and gel filtration by fast protein liquid chromatography on Superdex 75. Pomegranin was unadsorbed on DEAE-cellulose but adsorbed on Affi-gel blue gel. It exhibited a molecular mass of 11 kDa in both gel filtration and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. It inhibited mycelial growth in the fungi Botrytis cinerea and Fusarium oxysporum with an IC(50) of 2 microM and 6.1 microM, respectively. It was devoid of hemagglutinating, ribonuclease, deoxyribonuclease and protease inhibitory activities.

  10. EFFECT OF EXTRACTION METHODS ON ANTIFUNGAL ACTIVITY OF SEA CUCUMBER (Stichopus japonicus

    Directory of Open Access Journals (Sweden)

    Amir Husni

    2014-05-01

    Both SM and CS exhibited their highest antifungal activity when extracted by HRE with 70% ethanol and by HRE with water, respectively, while their highest yields were obtained when extracted by PSE with water. SM has more antifungal than potassium sorbate but weaker than propyl paraben, while CS has more antifungal than the two antifungal agents. Keywords: Antifungal, heat reflux extraction, pressurized solvent extraction, Stichopus japonicus

  11. Isobolographic Analysis of Pharmacodynamic Interactions between Antifungal Agents and Ciprofloxacin against Candida albicans and Aspergillus fumigatus▿

    OpenAIRE

    Stergiopoulou, Theodouli; Meletiadis, Joseph; Sein, Tin; Papaioannidou, Paraskevi; Tsiouris, Ioannis; Roilides, Emmanuel; Walsh, Thomas J.

    2008-01-01

    Patients suffering from invasive mycoses often receive concomitant antifungal therapy and antibacterial agents. Assessment of pharmacodynamic interactions between antifungal and antibacterial agents is complicated by the absence of a common antifungal end point for both agents. Ciprofloxacin has no intrinsic antifungal activity but may interact with antifungal agents, since it inhibits DNA gyrase (topoisomerase II), which is abundant in fungi. We therefore employed isobolographic analysis ada...

  12. Antifungal susceptibilities of bloodstream isolates of Candida species from nine hospitals in Korea: application of new antifungal breakpoints and relationship to antifungal usage.

    Directory of Open Access Journals (Sweden)

    Eun Jeong Won

    Full Text Available We applied the new clinical breakpoints (CBPs of the Clinical and Laboratory Standards Institute (CLSI to a multicenter study to determine the antifungal susceptibility of bloodstream infection (BSI isolates of Candida species in Korea, and determined the relationship between the frequency of antifungal-resistant Candida BSI isolates and antifungal use at hospitals. Four hundred and fifty BSI isolates of Candida species were collected over a 1-year period in 2011 from nine hospitals. The susceptibilities of the isolates to four antifungal agents were determined using the CLSI M27 broth microdilution method. By applying the species-specific CBPs, non-susceptibility to fluconazole was found in 16.4% (70/428 of isolates, comprising 2.6% resistant and 13.8% susceptible-dose dependent isolates. However, non-susceptibility to voriconazole, caspofungin, or micafungin was found in 0% (0/370, 0% (0/437, or 0.5% (2/437 of the Candida BSI isolates, respectively. Of the 450 isolates, 72 (16.0% showed decreased susceptibility to fluconazole [minimum inhibitory concentration (MIC ≥4 μg/ml]. The total usage of systemic antifungals varied considerably among the hospitals, ranging from 190.0 to 7.7 defined daily dose per 1,000 patient days, and fluconazole was the most commonly prescribed agent (46.3%. By Spearman's correlation analysis, fluconazole usage did not show a significant correlation with the percentage of fluconazole resistant isolates at hospitals. However, fluconazole usage was significantly correlated with the percentage of fluconazole non-susceptible isolates (r = 0.733; P = 0.025 or the percentage of isolates with decreased susceptibility to fluconazole (MIC ≥4 μg/ml (r = 0.700; P = 0.036 at hospitals. Our work represents the first South Korean multicenter study demonstrating an association between antifungal use and antifungal resistance among BSI isolates of Candida at hospitals using the new CBPs of the CLSI.

  13. Serial coupling of ion-exchange and size-exclusion chromatography to determine aggregation levels in mAbs in the presence of a proteinaceous excipient, recombinant human serum albumin.

    Science.gov (United States)

    Weisbjerg, Paul Luigi Gargani; Caspersen, Mikael Bjerg; Cook, Ken; Van De Weert, Marco

    2015-02-01

    Aggregation levels of therapeutic proteins may be difficult to determine in mixtures containing other proteinaceous excipients. We performed a feasibility study of using serial coupling of an anion exchange and size exclusion column to determine the aggregation levels of four different model monoclonal antibodies (mAb) mixed with the model proteinaceous excipient recombinant human serum albumin (rHSA). For three of the four mAbs suitable elution conditions could be established. From the limitations imposed by the pI of the rHSA, the pI of the mAb and the nature of the columns used, it was possible to propose a set of general conditions that allows quantification of the aggregation level of a therapeutic protein in the presence of a proteinaceous excipient: The excipient protein and protein of interest should differ in pI by a minimum of 0.5 units, and the pI of the protein of interest should not be higher than ca. 8.5.

  14. Effect of cultivation conditions on growth and antifungal activity of ...

    African Journals Online (AJOL)

    Administrator

    Growth and production of antifungal agent by Mycena leptocephala was investigated in ... plus glucose were used as carbon source and yeast extract was used as nitrogen source. .... basidiomycetes from wood – A review Int. Biodeterio. Bull.

  15. THE ANTIFUNGAL AND ANTIBACTERIAL ACTIVITY OF TWO PLANTS FROM ASTEMCEAE

    OpenAIRE

    2015-01-01

    In this study, we have found that, Chlysanthemum coronarium has shownantifungal and antibacterial activity, but Inula viscosa didn't show any antifungalor antibacterial activity.Key words: Chrysanthemum coronarium; Inula viscosa; antifungal andantibacterial activities.

  16. Combination antifungal therapy: a critical review of the evidence.

    Science.gov (United States)

    Ostrosky-Zeichner, L

    2008-05-01

    Invasive fungal infections have extremely high rates of morbidity and mortality, particularly in immunocompromised hosts. Combination antifungal therapy is conceptually attractive as a life-saving measure. However, in-vitro and in-vivo evidence is often conflicting and clinical trials in this area are limited. Most clinical studies show similar outcomes for combination antifungal therapy when compared to monotherapy, although secondary endpoints and sub-analyses often show advantages for the combinations in endpoints such as culture sterilisation. The logistics of large clinical trials of combination therapy are highly complex. Combination of antifungals with immune modulators is an exciting new research area. Until more data are available, clinicians should approach combination antifungal therapy with caution.

  17. Antifungal effect of (+)-pinoresinol isolated from Sambucus williamsii.

    Science.gov (United States)

    Hwang, Bomi; Lee, Juneyoung; Liu, Qing-He; Woo, Eun-Rhan; Lee, Dong Gun

    2010-05-14

    In this study, we investigated the antifungal activity and mechanism of action of (+)-pinoresinol, a biphenolic compound isolated from the herb Sambucus williamsii,used in traditional medicine. (+)-Pinoresinol displays potent antifungal properties without hemolytic effects on human erythrocytes. To understand the antifungal mechanism of (+)-pinoresinol, we conducted fluorescence experiments on the human pathogen Candida albicans. Fluorescence analysis using 1,6-diphenyl-1,3,5-hexatriene (DPH) indicated that the (+)-pinoresinol caused damage to the fungal plasma membrane. This result was confirmed by using rhodamine-labeled giant unilamellar vesicle (GUV) experiments. Therefore, the present study indicates that (+)-pinoresinol possesses fungicidal activities and therapeutic potential as an antifungal agent for the treatment of fungal infectious diseases in humans.

  18. Taxonomy and antifungal susceptibility of clinically important Rasamsonia species

    DEFF Research Database (Denmark)

    Houbraken, J.; Giraud, S.; Meijer, M.

    2013-01-01

    In recent years, Geosmithia argillacea has been increasingly reported in humans and animals and can be considered an emerging pathogen. The taxonomy of Geosmithia was recently studied, and Geosmithia argillacea and related species were transferred to the new genus Rasamsonia. The diversity among...... a set of Rasamsonia argillacea strains, including 28 clinical strains, was studied, and antifungal susceptibility profiles were generated. Data obtained from morphological studies and from phylogenetic analyses of internal transcribed spacer (ITS) and partial _-tubulin and calmodulin sequences revealed...... was the least active of the antifungals tested. The phenotypically similar species R. brevistipitata and R. cylindrospora had different antifungal susceptibility profiles, and this indicates that correct species identification is important to help guide appropriate antifungal therapy....

  19. Antifungal Effect of (+-Pinoresinol Isolated from Sambucus williamsii

    Directory of Open Access Journals (Sweden)

    Bomi Hwang

    2010-05-01

    Full Text Available In this study, we investigated the antifungal activity and mechanism of action of (+-pinoresinol, a biphenolic compound isolated from the herb Sambucus williamsii,used in traditional medicine. (+-Pinoresinol displays potent antifungal properties without hemolytic effects on human erythrocytes. To understand the antifungal mechanism of (+-pinoresinol, we conducted fluorescence experiments on the human pathogen Candida albicans. Fluorescence analysis using 1,6-diphenyl-1,3,5-hexatriene (DPH indicated that the (+-pinoresinol caused damage to the fungal plasma membrane. This result was confirmed by using rhodamine-labeled giant unilamellar vesicle (GUV experiments. Therefore, the present study indicates that (+-pinoresinol possesses fungicidal activities and therapeutic potential as an antifungal agent for the treatment of fungal infectious diseases in humans.

  20. Research to Identify Effective Antifungal Agents, 1993 Annual Report.

    Energy Technology Data Exchange (ETDEWEB)

    Schreck, Carl

    1993-10-01

    This study is a continuation of ``Research to Identify Effective Antifungal Agents'' sponsored by Bonneville Power Administration (Schreck et al. 1990, 1991, and 1992). The objectives of the present study were to select and evaluate candidate fungicides.

  1. Solubility, photostability and antifungal activity of phenylpropanoids encapsulated in cyclodextrins.

    Science.gov (United States)

    Kfoury, Miriana; Lounès-Hadj Sahraoui, Anissa; Bourdon, Natacha; Laruelle, Frédéric; Fontaine, Joël; Auezova, Lizette; Greige-Gerges, Hélène; Fourmentin, Sophie

    2016-04-01

    Effects of the encapsulation in cyclodextrins (CDs) on the solubility, photostability and antifungal activities of some phenylpropanoids (PPs) were investigated. Solubility experiments were carried out to evaluate the effect of CDs on PPs aqueous solubility. Loading capacities and encapsulation efficiencies of freeze-dried inclusion complexes were determined. Moreover, photostability assays for both inclusion complexes in solution and solid state were performed. Finally, two of the most widespread phytopathogenic fungi, Fusarium oxysporum and Botrytis cinerea, were chosen to examine the antifungal activity of free and encapsulated PPs. Results showed that encapsulation in CDs significantly increased the solubility and photostability of studied PPs (by 2 to 17-fold and 2 to 44-fold, respectively). Free PPs revealed remarkable antifungal properties with isoeugenol showing the lowest half-maximal inhibitory concentration (IC50) values of mycelium growth and spore germination inhibition. Encapsulated PPs, despite their reduced antifungal activity, could be helpful to solve drawbacks such as solubility and stability.

  2. Cryptic antifungal compounds active by synergism with polyene antibiotics.

    Science.gov (United States)

    Kinoshita, Hiroshi; Yoshioka, Mariko; Ihara, Fumio; Nihira, Takuya

    2016-04-01

    The majority of antifungal compounds reported so far target the cell wall or cell membrane of fungi, suggesting that other types of antibiotics cannot exert their activity because they cannot penetrate into the cells. Therefore, if the permeability of the cell membrane could be enhanced, many antibiotics might be found to have antifungal activity. We here used the polyene antibiotic nystatin, which binds to ergosterol and forms pores at the cell membrane, to enhance the cellular permeability. In the presence of nystatin, many culture extracts from entomopathogenic fungi displayed antifungal activity. Among all the active extracts, two active components were purified and identified as helvolic acid and terramide A. Because the minimum inhibitory concentration of either compound was reduced four-fold in the presence of nystatin, it can be concluded that this screening method is useful for detecting novel antifungal activity.

  3. Inhibition of Rat and Human Steroidogenesis by Triazole Antifungals

    Science.gov (United States)

    Environmental chemicals that alter steroid production could interfere with male reproductive development and function. Three agricultural antifungal triazoles (myclobutanil, propiconazole and triadimefon) that are known to modulate expression of cytochrome P450 (CYP) genes and e...

  4. Antifungal activity of Bacillus sp. isolated from compost.

    Science.gov (United States)

    Czaczyk, K; Stachowiak, B; Trojanowska, K; Gulewicz, K

    2000-01-01

    Four strains of Bacillus isolated from lupine compost exhibited an antifungal activity against six plant fungal pathogens (Rhizoctonia solani, Bipolaris sorokiniana, Sclerotinia sclerotiorum, Trichothecium roseum, Fusarium solani, Fusarium oxysporum). It was significantly influenced by the composition of the cultivation media.

  5. Antifungal activity of fruit pulp extract from Bromelia pinguin.

    Science.gov (United States)

    Camacho-Hernández, I L; Chávez-Velázquez, J A; Uribe-Beltrán, M J; Ríos-Morgan, A; Delgado-Vargas, F

    2002-08-01

    The methanol extract of the fruit pulp of Bromelia pinguin was evaluated for its antifungal activity. The extract showed a significant activity against some Trichophyton strains, although Candida strains were generally insensitive.

  6. In vitro investigation on antifungal activity of some plant extracts ...

    African Journals Online (AJOL)

    Prof. Ogunji

    Studies were carried out to determine the antifungal attributes of some plant extracts against Pyricularia oryzae. The plant species evaluated were the leaves of Ocimum gratissimum ..... of Pesticide Toxicology, New York, Academic. Press.

  7. Antifungal activity of hydrochloride salts of tylophorinidine and tylophorinine.

    Science.gov (United States)

    Dhiman, Mini; Parab, Rajashri R; Manju, Sreedharannair L; Desai, Dattatraya C; Mahajan, Girish B

    2012-09-01

    The antimicrobial efficacy of two phenanthroindolizidine alkaloids, tylophorinidine hydrochloride (TdnH) and tylophorinine hydrochloride (TnnH), isolated from the plant Tylophora indica (local name, Antamul) was evaluated. These were screened for in vitro antifungal and antibacterial activities. Both compounds exhibited potent antifungal activity displaying minimum inhibitory concentrations (MIC) in the range of 2-4 microg/mL for TdnH and 0.6-2.5 microg/mL for TnnH against Candida species.

  8. Antileishmanial, antimicrobial and antifungal activities of some new aryl azomethines.

    Science.gov (United States)

    Al-Kahraman, Yasser M S A; Madkour, Hassan M F; Ali, Dildar; Yasinzai, Masoom

    2010-01-28

    A series of eighteen azomethines has been synthesized by the reaction of appropriate primary aromatic amines with aryl and/or heteroaryl carboxaldehydes. The synthesized azomethines have been evaluated for their in vitro antileishmanial, antibacterial and antifungal activities. The results revealed some antifungal activity of most of the synthesized compounds, whereas the antileishmaniasis activity results highlighted that all synthesized azomethines inhibited parasite growth and most of them showed highly potent action towards Leishmania major promastigotes. No remarkable bactericidal activities were observed.

  9. Isolation of antifungally active lactobacilli from edam cheese

    DEFF Research Database (Denmark)

    Tuma, S.; Vogensen, Finn Kvist; Plocková, M.

    2007-01-01

    The antifungal activity of 322 lactobacilli strains isolated from Edam cheese at different stages of the ripening process was tested against Fusarium proliferatum M 5689 using a dual overlay spot assay. Approximately 21% of the isolates showed a certain level of inhibitory activity. Seven strains...... as Lb. paracasei and three as Lb. fermentum. Lb. paracasei ST 68 was chosen for further testing as antifungal protective adjunct for Edam cheese production.  ...

  10. Antifungal activity of propolis against Fonsecaea pedrosoi, a chromoblastomycosis agent

    OpenAIRE

    2011-01-01

    Chromoblastomycosis is a subcutaneous mycosis caused by dematiaceous fungi, being Fonsecaea pedrosoi the main etiologic agent in Brazil. Propolis is a resinous material collected by honeybees, with variable composition and pharmacological properties, including antifungal activity. The antifungal activity of ethanolic extracts of propolis (EEP) obtained from different municipalities of the state of Rio Grande do Sul, Brazil, against F. pedrosoi strains was assessed. The EEP showed MIC values b...

  11. 7-Chloroquinolin-4-yl Arylhydrazone Derivatives: Synthesis and Antifungal Activity

    Directory of Open Access Journals (Sweden)

    Auri R. Duval

    2011-01-01

    Full Text Available Fifteen 7-chloro-4-arylhydrazonequinolines have been evaluated for their in vitro antifungal activity against eight oral fungi: Candida albicans, C. parapsilosis, C. lipolytica, C. tropicalis, C. famata, C. glabrata, Rhodutorula mucilaginosa, and R. glutinis. Several compounds exhibited minimum inhibitory concentration (MIC and minimum fungicidal concentration (MFC activities comparable with the first-line drug fluconazole. These results could be considered as an important starting point for the rational design of new antifungal agents.

  12. A proteinaceous fraction of wheat bran may interfere in the attachment of enterotoxigenic E. coli K88 (F4+) to porcine epithelial cells.

    Science.gov (United States)

    González-Ortiz, Gemma; Bronsoms, Sílvia; Quarles Van Ufford, H C; Halkes, S Bart A; Virkola, Ritva; Liskamp, Rob M J; Beukelman, Cees J; Pieters, Roland J; Pérez, José Francisco; Martín-Orúe, Susana María

    2014-01-01

    Wheat bran (WB) from Triticum aestivum has many beneficial effects on human health. To the best of our knowledge, very little has been published about its ability to prevent pathogenic bacterial adhesion in the intestine. Here, a WB extract was fractionated using different strategies, and the obtained fractions were tested in different in vitro methodologies to evaluate their interference in the attachment of enterotoxigenic Escherichia coli (ETEC) K88 to intestinal porcine epithelial cells (IPEC-J2) with the aim of identifying the putative anti-adhesive molecules. It was found that a proteinaceous compound in the >300-kDa fraction mediates the recognition of ETEC K88 to IPEC-J2. Further fractionation of the >300-kDa sample by size-exclusion chromatography showed several proteins below 90 kDa, suggesting that the target protein belongs to a high-molecular-weight (MW) multi-component protein complex. The identification of some relevant excised bands was performed by mass spectrometry (MS) and mostly revealed the presence of various protease inhibitors (PIs) of low MW: Serpin-Z2B, Class II chitinase, endogenous alpha-amylase/subtilisin inhibitor and alpha-amylase/trypsin inhibitor CM3. Furthermore, an incubation of the WB extract with ETEC K88 allowed for the identification of a 7S storage protein globulin of wheat, Globulin 3 of 66 kDa, which may be one of the most firmly attached WB proteins to ETEC K88 cells. Further studies should be performed to gain an understanding of the molecular recognition of the blocking process that takes place. All gathered information can eventually pave the way for the development of novel anti-adhesion therapeutic agents to prevent bacterial pathogenesis.

  13. Millennial scale oscillations in bulk δ15N and δ13C over the Mid- to Late Holocene seen in proteinaceous corals from the North Pacific Subtropical Gyre

    Science.gov (United States)

    Glynn, D. S.; Mccarthy, M. D.; McMahon, K.; Guilderson, T. P.

    2014-12-01

    The North Pacific Subtropical Gyre (NPSG) is the largest continuous ecosystem on this planet and is an important regulator of biogeochemical cycling and carbon sequestration. With evidence of its expansion in a warming climate, it is necessary to develop a more complete understanding of the variability in productivity and nutrient dynamics in this important ecosystem through time. We constructed a long-term, high resolution record of bulk record of stable nitrogen (δ15N) and carbon isotopes (δ13C) from multiple proteinaceous deep sea corals around Hawaii extending back ~5300 years with few gaps. Our data confirms the decreasing trend in δ15N since the Little Ice Age (1850s), which matches previously published results in part attributed to anthropogenic climate change (e.g. Sherwood et al. 2014). However, while the rate of change since the Little Ice Age (δ15N declines ~1‰ over ~150yrs) remains by far the most rapid throughout the longer record, there also appear to be longer-term (near-millennial scale) climatic oscillations of even greater magnitude (δ15N shifts ~1.5-2‰ over ~1000yrs). After removal of the Seuss Effect, δ13C values also declined ~1.5‰ since the Little Ice Age. Furthermore, there also appear to be oscillations in δ13C of ~1-2‰ over millennial timescales. These results reveal the existence of previously unrecognized long-term oscillations in NPSG biogeochemical cycles, which are likely linked to changes in phytoplankton species composition, food web dynamics, and/or variability in source nutrients and productivity possibly caused by changes in climate. This study provides insight into nutrient dynamics in the NPSG over the past five millennia, and offers a historical baseline to better analyze the effects of current anthropogenic climate forcing.

  14. Potent heterologous antifungal proteins from cheeseweed (Malva parviflora).

    Science.gov (United States)

    Wang, X; Bunkers, G J

    2000-12-20

    Two novel antifungal proteins were purified and characterized from cheeseweed (Malva parviflora). Both proteins, designated CW-1 and CW-2, are composed of two different subunits of 5000 and 3000 Da, respectively. These proteins possess very potent antifungal activities, and more interestingly the inhibition is fungicidal instead of fungistatic. At low salt condition, the IC(50) of CW-1 and CW-2 against Fusarium graminearum (Fg) is 2.5 ppm. At high salt condition which diminishes the antifungal activity of many antifungal proteins, both CW-1 and CW-2 still maintain potent activity against Fg with IC(50) of 10 ppm. The two subunits could be separated by gel filtration in the presence of 6 M urea, but their antifungal activity cannot be recovered after the removal of urea. Amino acid sequence analysis indicates that both subunits of CW-1 show homology to 2S albumin, whereas the two subunits of CW-2 have homology to vicilin protein from cotton. To our knowledge, this is the first report of isolation and characterization of heterologous antifungal proteins from any source.

  15. An antifungal peptide from Phaseolus vulgaris cv. brown kidney bean

    Institute of Scientific and Technical Information of China (English)

    Yau Sang Chan; Jack Ho Wong; Evandro Fei Fang; Wen Liang Pan; Tzi Bun Ng

    2012-01-01

    A 5.4-kDa antifungal peptide,with an N-terminal sequence highly homologous to defensins and inhibitory activity against Mycosphaerella arachidicola (IC5o=3 μM),Setospaeria turcica and Bipolaris maydis,was isolated from the seeds of Phaseolus vulgaris cv.brown kidney bean.The peptide was purified by employing a protocol that entailed adsorption on Affi-gel blue gel and Mono S and finally gel filtration on Superdex 75.The antifungal activity of the peptide against M.arachidicola was stable in the pH range 3-12 and in the temperature range 0℃ to 80℃.There was a slight reduction of the antifungal activity at pH 2 and 13,and the activity was indiscernible at pH 0,1,and 14.The activity at 90℃ and 100℃ was slightly diminished.Deposition of Congo red at the hyphal tips of M.arachidicola was induced by the peptide indicating inhibition of hyphal growth.The lack of antiproliferative activity of brown kidney bean antifungal peptide toward tumor cells,in contrast to the presence of such activity of other antifungal peptides,indicates that different domains are responsible for the antifungal and antiproliferative activities.

  16. An antifungal peptide from Phaseolus vulgaris cv. brown kidney bean.

    Science.gov (United States)

    Chan, Yau Sang; Wong, Jack Ho; Fang, Evandro Fei; Pan, Wen Liang; Ng, Tzi Bun

    2012-04-01

    A 5.4-kDa antifungal peptide, with an N-terminal sequence highly homologous to defensins and inhibitory activity against Mycosphaerella arachidicola (IC(50)= 3 μM), Setospaeria turcica and Bipolaris maydis, was isolated from the seeds of Phaseolus vulgaris cv. brown kidney bean. The peptide was purified by employing a protocol that entailed adsorption on Affi-gel blue gel and Mono S and finally gel filtration on Superdex 75. The antifungal activity of the peptide against M. arachidicola was stable in the pH range 3-12 and in the temperature range 0°C to 80°C. There was a slight reduction of the antifungal activity at pH 2 and 13, and the activity was indiscernible at pH 0, 1, and 14. The activity at 90°C and 100°C was slightly diminished. Deposition of Congo red at the hyphal tips of M. arachidicola was induced by the peptide indicating inhibition of hyphal growth. The lack of antiproliferative activity of brown kidney bean antifungal peptide toward tumor cells, in contrast to the presence of such activity of other antifungal peptides, indicates that different domains are responsible for the antifungal and antiproliferative activities.

  17. The role of the multidisciplinary team in antifungal stewardship.

    Science.gov (United States)

    Agrawal, Samir; Barnes, Rosemary; Brüggemann, Roger J; Rautemaa-Richardson, Riina; Warris, Adilia

    2016-11-01

    There are a variety of challenges faced in the management of invasive fungal diseases (IFD), including high case-fatality rates, high cost of antifungal drugs and development of antifungal resistance. The diagnostic challenges and poor outcomes associated with IFD have resulted in excessive empirical use of antifungals in various hospital settings, exposing many patients without IFD to potential drug toxicities as well as causing spiralling antifungal drug costs. Further complexity arises as different patient groups show marked variation in their risk for IFD, fungal epidemiology, sensitivity and specificity of diagnostic tests and the pharmacokinetics and pharmacodynamics of antifungal drugs. To address these issues and to ensure optimal management of IFD, specialist knowledge and experience from a range of backgrounds is required, which extends beyond the remit of most antibiotic stewardship programmes. The first step in the development of any antifungal stewardship (AFS) programme is to build a multidisciplinary team encompassing the necessary expertise in the management of IFD to develop and implement the AFS programme. The specific roles of the key individuals within the AFS team and the importance of collaboration are discussed in this article.

  18. Antifungal effect and mechanism of garlic oil on Penicillium funiculosum.

    Science.gov (United States)

    Li, Wen-Ru; Shi, Qing-Shan; Liang, Qing; Huang, Xiao-Mo; Chen, Yi-Ben

    2014-10-01

    Garlic oil is a kind of fungicide, but little is known about its antifungal effects and mechanism. In this study, the chemical constituents, antifungal activity, and effects of garlic oil were studied with Penicillium funiculosum as a model strain. Results showed that the minimum fungicidal concentrations (MFCs, v/v) were 0.125 and 0.0313 % in agar medium and broth medium, respectively, suggesting that the garlic oil had a strong antifungal activity. The main ingredients of garlic oil were identified as sulfides, mainly including disulfides (36 %), trisulfides (32 %) and monosulfides (29 %) by gas chromatograph-mass spectrometer (GC/MS), which were estimated as the dominant antifungal factors. The observation results by transmission electron microscope (TEM) and scanning electron microscope (SEM) indicated that garlic oil could firstly penetrate into hyphae cells and even their organelles, and then destroy the cellular structure, finally leading to the leakage of both cytoplasm and macromolecules. Further proteomic analysis displayed garlic oil was able to induce a stimulated or weakened expression of some key proteins for physiological metabolism. Therefore, our study proved that garlic oil can work multiple sites of the hyphae of P. funiculosum to cause their death. The high antifungal effects of garlic oil makes it a broad application prospect in antifungal industries.

  19. Non-fusion soluble expression of broad-spectrum antivirus protein in Escherichia coli by translational-coupling with SUMO%利用翻译偶联实现广谱抗病毒蛋白在大肠杆菌中的可溶性表达

    Institute of Scientific and Technical Information of China (English)

    邢伶越; 谢德健; 叶丙雨; 张章; 李平; 沈文龙; 师明磊; 张彦; 赵志虎

    2015-01-01

    目的:以具有广泛助溶活性的小泛素相关修饰蛋白( small ubiquitin-related modifier,SUMO)为辅助蛋白,利用翻译偶联,构建一种新型非融合可溶原核表达载体,实现广谱抗病毒蛋白RA在大肠杆菌中的非融合可溶表达。方法以PCR方法从酵母基因组中克隆SUMO蛋白基因smt3并进行定点突变,去除其中的EcoRⅠ酶切位点,获得同义突变体mSUMO。通过翻译偶联Linker序列的设计、合成,构建以mSUMO蛋白为辅助蛋白的翻译偶联表达载体pTIG-mSUMO。 PCR扩增获得带有相应酶切位点的广谱抗病毒蛋白 RA 的基因,将其克隆至 pTIG-mSUMO中,获得表达载体pTIG-mSUMO/RA,实现RA在大肠杆菌中的非融合可溶性表达。结果 IPTG诱导蛋白表达以后,SDS-PAGE和Western印迹检测证实,目的蛋白RA的表达量明显增加,且可溶比例约占50%。结论以优化后的SUMO为辅助蛋白,成功构建了一种非融合的可溶原核表达载体pTIG-mSUMO,实现了RA蛋白在大肠杆菌中的高效非融合可溶表达,既提高了表达水平,也提高了可溶性。 pTIG-mSUMO作为一种可溶的非融合表达载体,在实现外源蛋白的高效可溶表达方面,很可能具有一定的普遍性。%Objective To design and construct a new non-fusion soluble expression vector pTIG-mSUMO(small ubiq-uitin-related modifier) using the widely used solubility promoting protein SUMO and based on the translational coupling phenomenon in order to enable the non-fusion soluble expression of the broad-spectrum antiviral protein RA in Escherichia coli by pTIG-mSUMO.Methods The smt3 gene coding for SUMO protein was cloned from yeast genome DNA by PCR. After directed-site silent mutation to eliminate the EcoRⅠsite, the mutant mSUMO was inserted into pET-22b to obtain the translational coupling expression vector pTIG-mSUMO.The RA was subject to PCR amplification and cloned into the pTIG-mSUMO to

  20. Nationwide study of candidemia, antifungal use, and antifungal drug resistance in Iceland, 2000 to 2011.

    Science.gov (United States)

    Asmundsdottir, Lena Ros; Erlendsdottir, Helga; Gottfredsson, Magnus

    2013-03-01

    Candidemia is often a life-threatening infection, with highly variable incidence among countries. We conducted a nationwide study of candidemia in Iceland from 2000 to 2011, in order to determine recent trends in incidence rates, fungal species distribution, antifungal susceptibility patterns, and concurrent antifungal consumption. A total of 208 infection episodes in 199 patients were identified. The average incidence during the 12 years was 5.7 cases/100,000 population/year, which was significantly higher than that from 1990 to 1999 (4.3/100,000/year; P = 0.02). A significant reduction in the use of blood cultures was noted in the last 3 years of the study, coinciding with the economic crisis in the country (P 60 years, and varied by gender. Age-specific incidence among males >80 years old was 28.6/100,000/year, and it was 8.3/100,000/year for females in this age group (P = 0.028). The 30-day survival rate among adult patients remained unchanged compared to that from 1990 to 1999 (70.4% versus 69.5%, P = 0.97). Candida albicans was the predominant species (56%), followed by C. glabrata (16%) and C. tropicalis (13%). The species distribution remained stable compared to that from previous decades. Fluconazole use increased 2.4-fold from 2000 to 2011, with no increase in resistance. In summary, the incidence of candidemia in Iceland has continued to increase but may have reached a steady state, and no increase in antifungal drug resistance has been noted. Decreased use of blood cultures toward the end of the study may have influenced detection rates.

  1. Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2005: an 8.5-Year Analysis of Susceptibilities of Candida Species and Other Yeast Species to Fluconazole and Voriconazole Determined by CLSI Standardized Disk Diffusion Testing▿

    Science.gov (United States)

    Pfaller, M. A.; Diekema, D. J.; Gibbs, D. L.; Newell, V. A.; Meis, J. F.; Gould, I. M.; Fu, W.; Colombo, A. L.; Rodriguez-Noriega, E.

    2007-01-01

    Fluconazole in vitro susceptibility test results for 205,329 yeasts were collected from 134 study sites in 40 countries from June 1997 through December 2005. Data were collected for 147,776 yeast isolates tested with voriconazole from 2001 through 2005. All investigators tested clinical yeast isolates by the CLSI M44-A disk diffusion method. Test plates were automatically read and results recorded with a BIOMIC image analysis system. Species, drug, zone diameter, susceptibility category, and quality control results were collected quarterly. Duplicate (same patient, same species, and same susceptible-resistant biotype profile during any 7-day period) and uncontrolled test results were not analyzed. Overall, 90.1% of all Candida isolates tested were susceptible (S) to fluconazole; however, 10 of the 22 species identified exhibited decreased susceptibility (<75% S) on the order of that seen with the resistant (R) species C. glabrata and C. krusei. Among 137,487 isolates of Candida spp. tested against voriconazole, 94.8% were S and 3.1% were R. Less than 30% of fluconazole-resistant isolates of C. albicans, C. glabrata, C. tropicalis, and C. rugosa remained S to voriconazole. The non-Candida yeasts (8,821 isolates) were generally less susceptible to fluconazole than Candida spp. but, aside from Rhodotorula spp., remained susceptible to voriconazole. This survey demonstrates the broad spectrum of these azoles against the most common opportunistic yeast pathogens but identifies several less common yeast species with decreased susceptibility to antifungal agents. These organisms may pose a future threat to optimal antifungal therapy and emphasize the importance of prompt and accurate species identification. PMID:17442797

  2. Proteinaceous alpha-araylase inhibitors

    DEFF Research Database (Denmark)

    Svensson, Birte; Fukuda, Kenji; Nielsen, P.K.

    2004-01-01

    Proteins that inhibit alpha-amylases have been isolated from plants and microorganisms. These inhibitors can have natural roles in the control of endogenous a-amylase activity or in defence against pathogens and pests; certain inhibitors are reported to be antinutritional factors. The alpha-amylase...... inhibitors belong to seven different protein structural families, most of which also contain evolutionary related proteins without inhibitory activity. Two families include bifunctional inhibitors acting both on alpha-amylases and proteases. High-resolution structures are available of target alpha-amylases...... in complex with inhibitors from five families. These structures indicate major diversity but also some similarity in the structural basis of alpha-amylase inhibition. Mutational analysis of the mechanism of inhibition was performed in a few cases and various protein engineering and biotechnological...

  3. Antifungal activity of plant extracts against dermatophytes.

    Science.gov (United States)

    Ali-Shtayeh, M S; Abu Ghdeib, S I

    1999-01-01

    The aqueous extracts (15 micrograms ml-1 medium) of 22 plants used in folkloric medicine in Palestine were investigated for their antifungal activity and minimum inhibitory concentrations (MICs) against nine isolates of Microsporum canis, Trichophyton mentagrophytes and Trichophyton violaceum. The extract of the different plant species reduced colony growth of the three dermatophytes by 36 to 100% compared with the control treatment. Antimycotic activity of the extract against the three dermatophytes varied significantly (P Inula viscosa, J. regia and P. lentiscus against T. mentagrophytes; and Asphodelus luteus, A. arvensis, C. spinosa, Clematis cirrhosa, I. viscosa, J. regia, P. lentiscus, Plumbago europea, Ruscus aculeatus, Retema raetam and Salvia fruticosa against T. violaceum. The MICs of these most active plants ranged from 0.6 to 40 micrograms ml-1. The three dermatophytes differed significantly with regard to their susceptibility to plant extracts. Trichophyton violaceum was the most susceptible being completely inhibited by 50% of the extracts followed by M. canis and T. mentagrophytes which were completely inhibited by only 23 and 14% of the extracts, respectively.

  4. Antifungal and molluscicidal saponins from Serjania salzmanniana.

    Science.gov (United States)

    Ekabo, O A; Farnsworth, N R; Henderson, T O; Mao, G; Mukherjee, R

    1996-04-01

    An investigation of Serjania salzmanniana for biologically active substances has led to the isolation of two novel saponins, salzmannianoside A (3-O-[[beta-D- glucopyranosyl-(1-->4)]-[alpha-L-rhamnopyranosyl-(1-->2)]-alpha-L- arabinopyranosyl] gypsogenin) [3] and salzmannianoside B (3-O-[[beta-D-glucopyranosyl-(1-->4)]-[alpha-L- arabinopyranosyl-(1-->3)-alpha-L-rhamnopyranosyl-(1-->2)] -alpha-L-arabinopyranosyl] hederagenin) (4). Two known saponins, pulsatilla saponin D (3-O-[[beta-D- glucopyranosyl-(1-->4)]-[alpha-L-rhamnopyranosyl-(1-->2)]-alpha-L- arabinopyranosyl] hederagenin) (1) and 3-O-[[beta-D-glucopyranosyl-(1-->4)]-[alpha-L-rhamnopyranosyl-(1-->2)]-a lpha-L- arabinopyranosyl] oleanolic acid (2) were also isolated from this plant. The structures of 3 and 4 were elucidated by FABMS and 2D NMR techniques. All these four saponins were mollusicidal, causing 70-100% mortality at 10 ppm against Biomphalaria alexandrina, a vector of Schistosoma mansoni in the Nile Valley. The saponins also showed antifungal activity against Cryptococcus neoformans and Candida albicans at minimal inhibitory concentrations of 8 and 16 micrograms/mL, respectively.

  5. Macrocyclic trichothecenes as antifungal and anticancer compounds.

    Science.gov (United States)

    de Carvalho, Maira Peres; Weich, Herbert; Abraham, Wolf-Rainer

    2016-01-01

    Trichothecenes are sesquiterpenoid metabolites produced by fungi and species of the plant genus Baccharis, family Asteraceae. They comprise a tricyclic core with an epoxide at C-12 and C-13 and can be grouped into non-macrocyclic and macrocyclic compounds. While many of these compounds are of concern in agriculture, the macrocyclic metabolites have been evaluated as antiviral, anti-cancer, antimalarial and antifungal compounds. Some known cytotoxic responses on eukaryotic cells include inhibition of protein, DNA and RNA syntheses, interference with mitochondrial function, effects on cell division and membranes. These targets however have been elucidated essentially employing non-macrocyclic trichothecenes and only one or two closely related macrocyclic compounds. For several macrocyclic trichothecenes high selectivity against fungal species and against cancer cell lines have been reported suggesting that the macrocycle and its stereochemistry are of crucial importance regarding biological activity and selectivity. This review is focused on compounds belonging to the macrocyclic type, where a cyclic diester or triester ring binds to the trichothecane moiety at C-4 and C- 15 leading to natural products belonging to the groups of satratoxins, verrucarins, roridins, myrotoxins and baccharinoids. Their biological activities, cytotoxic mechanisms and structure-activity relationships (SAR) are discussed. From the reported data it becomes evident that even small changes in the molecules can lead to pronounced effects on biological activity or selectivity against cancer cells lines. Understanding the underlying mechanisms may help to design highly specific drugs for cancer therapy.

  6. Probiotics as Antifungals in Mucosal Candidiasis.

    Science.gov (United States)

    Matsubara, Victor H; Bandara, H M H N; Mayer, Marcia P A; Samaranayake, Lakshman P

    2016-05-01

    Candidais an opportunistic pathogen that causes mucosal and deep systemic candidiasis. The emergence of drug resistance and the side effects of currently available antifungals have restricted their use as long-term prophylactic agents for candidal infections. Given this scenario, probiotics have been suggested as a useful alternative for the management of candidiasis. We analyzed the available data on the efficacy of probiotics in candidal colonization of host surfaces. A number of well-controlled studies indicate that probiotics, particularly lactobacilli, suppressCandidagrowth and biofilm development in vitro.A few clinical trials have also shown the beneficial effects of probiotics in reducing oral, vaginal, and enteric colonization byCandida; alleviation of clinical signs and symptoms; and, in some cases, reducing the incidence of invasive fungal infection in critically ill patients. Probiotics may serve in the future as a worthy ally in the battle against chronic mucosal candidal infections. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  7. Antifungal prophylaxis in stem cell transplantation centers in Turkey

    Directory of Open Access Journals (Sweden)

    Hamdi Akan

    2011-12-01

    Full Text Available Objective: This study aimed to determine the current state of antifungal prophylaxis in Turkish stem cell transplantation (SCT centers. Materials and Methods: The were 38 active stem cell transplantation centers in Turkey, 28 of which were registered with the European Group for Blood and Marrow Transplantation (EBMT. Survey questionnaires were sent to the 28 EBMT centers in an effort to collect data on antifungal prophylaxis in different settings. In all, 24 of the centers completed the survey; 1 of the 24 centers was excluded from the study, as it was under construction at the time and was not performing transplantation.Results: In all, 15 (65% of the 23 centers were adult SCT centers, 7 (31% were pediatric SCT centers, and 1 center treated both adult and pediatric patients. All centers (23/23 performed both allogeneic and autologous transplants, 20 centers performed non-myeloablative transplants, 8 performed cord blood transplants, and 7 performed unrelated transplants. Primary antifungal prophylaxis was used at all 23 centers during allogeneic transplants, whereas 18 of the 23 centers used it during every autologous transplant and 2 of the 23 centers used it during autologous transplants on a per case basis. The most common drug used for prophylaxis was fluconazole (F (21/23, followed by itraconazole (I (3/23, amphotericin-B (2/23, and posaconazole (1/23. Among the 23 centers, 3 reported that for allogenic transplants they changed the antifungal prophylactic in cases of graft versus host disease (GVHD, and 12 of the 23 centers reported that they changed the antifungal prophylactic in case of nearby construction. All 23 centers performed secondary prophylaxis. Conclusion: Antifungal prophylaxis for hematopoetic SCT patients was the standard protocol in the 23 centers included in the study, usually with such azoles as F. The introduction of posaconazole in Turkey and the potential approval of voriconazole for antifungal prophylaxis will