The genetic basis of fluconazole resistance development in Candida albicans

Biochim Biophys Acta. 2002 Jul 18;1587(2-3):240-8. doi: 10.1016/s0925-4439(02)00087-x.

Abstract

Infections by the opportunistic fungal pathogen Candida albicans are widely treated with the antifungal agent fluconazole that inhibits the biosynthesis of ergosterol, the major sterol in the fungal plasma membrane. The emergence of fluconazole-resistant C. albicans strains is a significant problem after long-term treatment of recurrent oropharyngeal candidiasis (OPC) in acquired immunodeficiency syndrome (AIDS) patients. Resistance can be caused by alterations in sterol biosynthesis, by mutations in the drug target enzyme, sterol 14alpha-demethylase (14DM), which lower its affinity for fluconazole, by increased expression of the ERG11 gene encoding 14DM, or by overexpression of genes coding for membrane transport proteins of the ABC transporter (CDR1/CDR2) or the major facilitator (MDR1) superfamilies. Different mechanisms are frequently combined to result in a stepwise development of fluconazole resistance over time. The MDR1 gene is not or barely transcribed during growth in vitro in fluconazole-susceptible C. albicans strains, but overexpressed in many fluconazole-resistant clinical isolates, resulting in reduced intracellular fluconazole accumulation. The activation of the gene in resistant isolates is caused by mutations in as yet unknown trans-regulatory factors, and the resulting constitutive high level of MDR1 expression causes resistance to other toxic compounds in addition to fluconazole. Disruption of both alleles of the MDR1 gene in resistant C. albicans isolates abolishes their resistance to these drugs, providing genetic evidence that MDR1 mediates multidrug resistance in C. albicans.

Publication types

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

MeSH terms

  • AIDS-Related Opportunistic Infections / drug therapy
  • Antifungal Agents / pharmacology*
  • Candida albicans / drug effects*
  • Candida albicans / genetics
  • Candidiasis / complications
  • Candidiasis / drug therapy
  • Drug Resistance, Fungal / genetics
  • Drug Resistance, Multiple / genetics
  • Fluconazole / pharmacology*
  • Gene Expression
  • Genes, Fungal
  • Genes, MDR
  • Humans
  • Mutation

Substances

  • Antifungal Agents
  • Fluconazole