Identification and characterization of antifungal compounds using a Saccharomyces cerevisiae reporter bioassay

Par Conseil national de recherches du Canada

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DOI	Trouver le DOI : https://doi.org/10.1371/journal.pone.0036021
Auteur	Rechercher : Tebbets, Brad; Rechercher : Stewart, Douglas; Rechercher : Lawry, Stephanie; Rechercher : Nett, Jeniel; Rechercher : Nantel, Andre¹; Rechercher : Andes, David; Rechercher : Klein, Bruce S.
Affiliation	Conseil national de recherches du Canada. Institut de recherche en biotechnologie du CNRC
Format	Texte, Article
Sujet	amphotericin B; antifungal agent; cortisone; fluconazole; fludioxonil; antifungal agent; protein histidine kinase; protein kinase; antifungal activity; Aspergillus fumigatus; bioassay; biofilm; Candida albicans; candidiasis; colony forming unit; Cryptococcus; disk diffusion; down regulation; drug potency; drug screening; drug structure; drug targeting; fungal strain; fungus growth; genetic transcription; high throughput screening; Magnaporthe grisea; microarray analysis; minimum inhibitory concentration; oxidative stress; protein expression; rat; Rhizopus oryzae; Saccharomyces cerevisiae; single drug dose; upregulation; antifungal resistance; DNA damage; DNA microarray; DNA repair; drug effect; drug potentiation; reporter gene; Candida; Mammalia; Biological Assay; Drug Evaluation, Preclinical; Drug Resistance, Fungal; Drug Synergism; Microbial Sensitivity Tests; Oligonucleotide Array Sequence Analysis
Résumé	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.
Date de publication	2012-05-04
Dans	PLoS ONE 7, nº 5 (4 mai 2012) : e36021-1–e36021-11.
Langue	anglais
Publications évaluées par des pairs	Oui
Numéro du CNRC	NRCC 53171
Numéro NPARC	20097241
Exporter la notice	Exporter en format RIS
Signaler une correction	Signaler une correction (s'ouvre dans un nouvel onglet)
Identificateur de l’enregistrement	5ea6d4bb-d768-4a36-8250-e5949a53d2ec
Enregistrement créé	2012-06-07
Enregistrement modifié	2020-04-21

Date de modification :: 2024-07-19