Metabolic control of antifungal drug resistance

Fungal Genet Biol. 2010 Feb;47(2):81-93. doi: 10.1016/j.fgb.2009.07.004. Epub 2009 Jul 10.


Fungi have evolved an elegant repertoire of mechanisms to survive the cellular stress exerted by antifungal drugs such as azoles, which inhibit ergosterol biosynthesis inducing cell membrane stress. The evolution and maintenance of diverse resistance phenotypes is contingent upon cellular circuitry regulated by the molecular chaperone Hsp90 and its client protein calcineurin. Here, we establish a novel role for nutrients and nutrient signaling in azole resistance. The vulnerability of Saccharomyces cerevisiae azole resistance phenotypes to perturbation was contingent upon specific auxotrophies. Using strains that acquired azole resistance by Erg3 loss of function as a model for resistance that depends on cellular stress responses, we delineated genetic and environmental factors that mitigate the translation of genotype into resistance phenotype. Compromising a global regulator that couples growth and metabolism to environmental cues, Tor kinase, provides a powerful strategy to abrogate drug resistance of S. cerevisiae and Candida albicans with broad therapeutic potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism
  • Antifungal Agents / pharmacology*
  • Azoles / pharmacology*
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Calcineurin / genetics
  • Calcineurin / metabolism
  • Culture Media / chemistry
  • Drug Resistance, Fungal / drug effects
  • Drug Resistance, Fungal / genetics
  • Drug Resistance, Fungal / physiology*
  • Gene Expression
  • Genome, Fungal / genetics
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Microbial Sensitivity Tests
  • Mutation
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism
  • Phenotype
  • Reverse Transcriptase Polymerase Chain Reaction
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology


  • Amino Acids
  • Antifungal Agents
  • Azoles
  • Basic-Leucine Zipper Transcription Factors
  • Culture Media
  • GCN4 protein, S cerevisiae
  • HSP82 protein, S cerevisiae
  • HSP90 Heat-Shock Proteins
  • Saccharomyces cerevisiae Proteins
  • Oxidoreductases
  • sterol delta-5 desaturase
  • Calcineurin
  • Sirolimus