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.
Kontoyiannis
D P
DP
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
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