Defective sterol C5-6 desaturation and azole resistance: a new hypothesis for the mode of action of azole antifungals

Biochem Biophys Res Commun. 1989 Nov 15;164(3):1170-5. doi: 10.1016/0006-291x(89)91792-0.


Two azole resistant isolates of Saccharomyces cerevisiae carried mutations allelic to erg 3 and were blocked to differing degrees at the C5-6 desaturation step of ergosterol biosynthesis. When treated with the sterol 14 alpha-demethylation inhibitor fluconazole the wild-type sensitive strain accumulated lanosterol and 14 alpha-methyl-erogosta-8,24(28)-dien-3 beta, 6 alpha-diol (14-methyl-3,6 diol). The stringent desaturase mutant, A2, accumulated 14 alpha-methyl-8,24(28)-dien-3 beta-ol (14-methyl fecosterol) and lanosterol as the major sterol components when treated with fluconazole. Resistant isolate A3 accumulated 14-methyl-3,6-diol, 14-methyl fecosterol, and lanosterol and was only partially blocked at sterol C5-6 desaturation. We conclude that functional sterol C5-6 desaturase is required for the synthesis of 14-methyl-3,6-diol under conditions of azole inhibition. We present a new hypothesis for the mode of action of azole antifungals based on the inability of 14-methyl-3,6-diol to support growth, and suggest that growth can occur through utilisation of 14-methyl fecosterol, produced by a combination of azole inhibition and defective sterol C5-6 desaturation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / pharmacology*
  • Azoles / pharmacology*
  • Drug Resistance, Microbial / genetics
  • Fluconazole / pharmacology*
  • Gas Chromatography-Mass Spectrometry
  • Mutation
  • Oxidoreductases / genetics*
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics*
  • Sterols / metabolism*


  • Antifungal Agents
  • Azoles
  • Sterols
  • Fluconazole
  • Oxidoreductases
  • sterol delta-5 desaturase