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Identification and Characterization of Antifungal Compounds Using a Saccharomyces cerevisiae Reporter Bioassay
New antifungal drugs are urgently needed due to the currently limited selection, the emergence of drug resistance, and the toxicity of several commonly used drugs. To identify drug leads, we screened small molecules using a Saccharomyces cerevisiae reporter bioassay in which S. cerevisiae heterologo...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3344848/ https://www.ncbi.nlm.nih.gov/pubmed/22574132 http://dx.doi.org/10.1371/journal.pone.0036021 |
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author | Tebbets, Brad Stewart, Douglas Lawry, Stephanie Nett, Jeniel Nantel, Andre Andes, David Klein, Bruce S. |
author_facet | Tebbets, Brad Stewart, Douglas Lawry, Stephanie Nett, Jeniel Nantel, Andre Andes, David Klein, Bruce S. |
author_sort | Tebbets, Brad |
collection | PubMed |
description | New antifungal drugs are urgently needed due to the currently limited selection, the emergence of drug resistance, and the toxicity of several commonly used drugs. To identify drug leads, we screened small molecules using a Saccharomyces cerevisiae reporter bioassay in which S. cerevisiae heterologously expresses Hik1, a group III hybrid histidine kinase (HHK) from Magnaporthe grisea. Group III HHKs are integral in fungal cell physiology, and highly conserved throughout this kingdom; they are absent in mammals, making them an attractive drug target. Our screen identified compounds 13 and 33, which showed robust activity against numerous fungal genera including Candida spp., Cryptococcus spp. and molds such as Aspergillus fumigatus and Rhizopus oryzae. Drug-resistant Candida albicans from patients were also highly susceptible to compounds 13 and 33. While the compounds do not act directly on HHKs, microarray analysis showed that compound 13 induced transcripts associated with oxidative stress, and compound 33, transcripts linked with heavy metal stress. Both compounds were highly active against C. albicans biofilm, in vitro and in vivo, and exerted synergy with fluconazole, which was inactive alone. Thus, we identified potent, broad-spectrum antifungal drug leads from a small molecule screen using a high-throughput, S. cerevisiae reporter bioassay. |
format | Online Article Text |
id | pubmed-3344848 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33448482012-05-09 Identification and Characterization of Antifungal Compounds Using a Saccharomyces cerevisiae Reporter Bioassay Tebbets, Brad Stewart, Douglas Lawry, Stephanie Nett, Jeniel Nantel, Andre Andes, David Klein, Bruce S. PLoS One Research Article New antifungal drugs are urgently needed due to the currently limited selection, the emergence of drug resistance, and the toxicity of several commonly used drugs. To identify drug leads, we screened small molecules using a Saccharomyces cerevisiae reporter bioassay in which S. cerevisiae heterologously expresses Hik1, a group III hybrid histidine kinase (HHK) from Magnaporthe grisea. Group III HHKs are integral in fungal cell physiology, and highly conserved throughout this kingdom; they are absent in mammals, making them an attractive drug target. Our screen identified compounds 13 and 33, which showed robust activity against numerous fungal genera including Candida spp., Cryptococcus spp. and molds such as Aspergillus fumigatus and Rhizopus oryzae. Drug-resistant Candida albicans from patients were also highly susceptible to compounds 13 and 33. While the compounds do not act directly on HHKs, microarray analysis showed that compound 13 induced transcripts associated with oxidative stress, and compound 33, transcripts linked with heavy metal stress. Both compounds were highly active against C. albicans biofilm, in vitro and in vivo, and exerted synergy with fluconazole, which was inactive alone. Thus, we identified potent, broad-spectrum antifungal drug leads from a small molecule screen using a high-throughput, S. cerevisiae reporter bioassay. Public Library of Science 2012-05-04 /pmc/articles/PMC3344848/ /pubmed/22574132 http://dx.doi.org/10.1371/journal.pone.0036021 Text en Tebbets et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Tebbets, Brad Stewart, Douglas Lawry, Stephanie Nett, Jeniel Nantel, Andre Andes, David Klein, Bruce S. Identification and Characterization of Antifungal Compounds Using a Saccharomyces cerevisiae Reporter Bioassay |
title | Identification and Characterization of Antifungal Compounds Using a Saccharomyces cerevisiae Reporter Bioassay |
title_full | Identification and Characterization of Antifungal Compounds Using a Saccharomyces cerevisiae Reporter Bioassay |
title_fullStr | Identification and Characterization of Antifungal Compounds Using a Saccharomyces cerevisiae Reporter Bioassay |
title_full_unstemmed | Identification and Characterization of Antifungal Compounds Using a Saccharomyces cerevisiae Reporter Bioassay |
title_short | Identification and Characterization of Antifungal Compounds Using a Saccharomyces cerevisiae Reporter Bioassay |
title_sort | identification and characterization of antifungal compounds using a saccharomyces cerevisiae reporter bioassay |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3344848/ https://www.ncbi.nlm.nih.gov/pubmed/22574132 http://dx.doi.org/10.1371/journal.pone.0036021 |
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