Genomewide Elucidation of Drug Resistance Mechanisms for Systemically Used Antifungal Drugs Amphotericin B, Caspofungin, and Voriconazole in the Budding Yeast

0508417 - FGÚ 2020 RIV US eng J - Journal Article
Balkan, C. - Ercan, I. - Isik, E. - Akdeniz, E. S. - Balcioglu, O. - Kodedová, Marie - Zimmermannová, Olga - Dundar, M. - Sychrová, Hana - Koc, A.
Genomewide Elucidation of Drug Resistance Mechanisms for Systemically Used Antifungal Drugs Amphotericin B, Caspofungin, and Voriconazole in the Budding Yeast.
Antimicrobial Agents and Chemotherapy. Roč. 63, č. 9 (2019), č. článku e02268-18. ISSN 0066-4804. E-ISSN 1098-6596
Institutional support: RVO:67985823
Keywords : amphotericin B * antifungal agents * caspofungin * drug resistence * genomics * multidrug resistence * voriconazole
OECD category: Microbiology
Impact factor: 4.904, year: 2019
Method of publishing: Open access
https://aac.asm.org/content/63/9/e02268-18

There are only a few antifungal drugs used systemically in treatment, and invasive fungal infections that are resistant to these drugs are an emerging problem in health care. In this study, we performed a high-copy-number genomic DNA (gDNA) library screening to find and characterize genes that reduce susceptibility to amphotericin B, caspofungin, and voriconazole in Saccharomyces cerevisiae. We identified the PDR16 and PMP3 genes for amphotericin B, the RMD9 and SWH1 genes for caspofungin, and the MRS3 and TRI1 genes for voriconazole. The deletion mutants for PDR16 and PMP3 were drug susceptible, but the other mutants had no apparent susceptibility. Quantitative-PCR analyses suggested that the corresponding drugs upregulated expression of the PDR16, PMP3, SWH1, and MRS3 genes. To further characterize these genes, we also profiled the global expression patterns of the cells after treatment with the antifungals and determined the genes and paths that were up-or downregulated. We also cloned Candida albicans homologs of the PDR16, PMP3, MRS3, and TRI1 genes and expressed them in S. cerevisiae. Heterologous expression of Candida homologs also provided reduced drug susceptibility to the budding yeast cells. Our analyses suggest the involvement of new genes in antifungal drug resistance.
Permanent Link: http://hdl.handle.net/11104/0299329