Modulation of fluconazole sensitivity by the interaction of mitochondria and erg3p in Saccharomyces cerevisiae

J Antimicrob Chemother. 2000 Aug;46(2):191-7. doi: 10.1093/jac/46.2.191.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antifungal Agents / pharmacology*
  • Culture Media
  • Drug Resistance, Microbial
  • Ergosterol / analogs & derivatives
  • Ergosterol / metabolism
  • Fluconazole / pharmacology*
  • Microbial Sensitivity Tests
  • Mitochondria / drug effects*
  • Mutation / genetics
  • Oxidative Phosphorylation
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism*
  • Saccharomyces cerevisiae / drug effects*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Sterols / metabolism

Substances

  • 14-methylfecosterol
  • Antifungal Agents
  • Culture Media
  • Sterols
  • Fluconazole
  • Oxidoreductases
  • sterol delta-5 desaturase
  • Ergosterol