Modulation of fluconazole sensitivity by the interaction of mitochondria and erg3p in Saccharomyces cerevisiae.
We studied the effects of fluconazole, an ergosterol-depleting agent, in Saccharomyces cerevisiae, a genetically tractable fungus closely related to Candida albicans. The wild-type Saccharomyces strain was sensitive to fluconazole, but the isogenic cytoplasmic petite mutant (rho-) was resistant. The mechanism of resistance of rho- mutants appeared to involve uncoupling of oxidative phosphorylation. However, the petite strain with a mutation in cent5, 6 desaturase (erg3 rho-) was sensitive to fluconazole, in contrast to its erg3 rho+ counterpart. It is known that erg3 mutants are azole resistant through the accumulation of 14-methyl-fecosterol, a less toxic ergosterol intermediate. These results indicate that mitochondria function as important physiological partners with Erg3p in the accumulation of toxic sterol intermediates in the presence of azoles.
The University of Texas M. D. Anderson Cancer Center, Section of Infectious Diseases, 1515 Holcombe Boulevard, Box 47, Houston, TX 77030, USA. dkontoyi@notes.mdacc.tmc.edu
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D000935:Antifungal Agents / Q000494:pharmacology*; D003470:Culture Media; D004352:Drug Resistance, Microbial; D004875:Ergosterol / Q000031:analogs & derivatives / Q000378:metabolism; D015725:Fluconazole / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008928:Mitochondria / Q000187:drug effects*; D009154:Mutation / Q000235:genetics; D010085:Oxidative Phosphorylation; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013261:Sterols / Q000378:metabolism
C414402:14-methylfecosterol; D000935:Antifungal Agents; D003470:Culture Media; D013261:Sterols; D015725:Fluconazole; D010088:Oxidoreductases; C039306:sterol delta-5 desaturase; D004875:Ergosterol