Efflux-mediated resistance to fluconazole could be modulated by sterol homeostasis in Saccharomyces cerevisiae.
Saccharomyces cerevisiae has long been used as a model organism in the study of the ergosterol pathway and its inhibitors. The Pdr5 protein (Pdr5p), an ATP binding cassette transporter, plays an important role in active efflux of azole antifungals and therefore in azole sensitivity and resistance in S. cerevisiae. We have identified the Fluconazole Dominant Resistance-1 (FDR-1) mutant, which has a single dominant mutation conferring high-level resistance to fluconazole. FDR-1 has been found to be an activated allele of the Pleiotropic Drug Resistance-1 (PDR-1) gene (termed PDR1-100) and to upregulate PDR5 transcription. Resistance of PDR1-100 to fluconazole decreased in the background of mutations known to affect sterol homeostasis. Hence, the resistance to fluconazole of PDR1-100 was paradoxically decreased in an erg3 PDR1-100 double mutant. The erg3 mutants are resistant to azoles and accumulate 14-methyl-fecosterol instead of ergosterol in the presence of azoles. These results reinforce the emerging evidence in both S. cerevisiae and Candida albicans that sterols could serve as substrates for Pdr5p for transport across membranes.
Department of Medical Specialties, Section of Infectious Diseases, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 47, Houston, TX 77030, USA. dkontoyi@notes.mdacc.tmc.edu
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D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000935:Antifungal Agents / Q000378:metabolism* / Q000494:pharmacology*; D003001:Cloning, Molecular; D003470:Culture Media; D004268:DNA-Binding Proteins / Q000235:genetics; D004352:Drug Resistance, Microbial; D004875:Ergosterol / Q000378:metabolism; D015725:Fluconazole / Q000378:metabolism* / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D013261:Sterols / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors
D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D003470:Culture Media; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C085480:PDR1 protein, S cerevisiae; C092438:PDR5 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D013261:Sterols; D015534:Trans-Activators; D014157:Transcription Factors; D015725:Fluconazole; D004875:Ergosterol