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 stud y of the ergosterol pathway and its inhibitors. The Pdr5 protein (Pdr5p), a n ATP binding cassette transporter, plays an Important role in active efflu x of azole antifungals and therefore in azole sensitivity and resistance in S. cerevisiae. We have identified the Fluconazole Dominant Resistance-1 (F DR-1) mutant, which has a single dominant mutation conferring high-level re sistance 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 upr egulate 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 az oles. These results reinforce the emerging evidence in both S. cerevisiae a nd Candida albicans that sterols could serve as substrates for Pdr5p for tr ansport across membranes.