Terbinafine resistance mediated by salicylate 1-monooxygenase in Aspergillus nidulans

Antimicrob Agents Chemother. 2004 Sep;48(9):3530-5. doi: 10.1128/AAC.48.9.3530-3535.2004.

Abstract

Resistance to antifungal agents is a recurring and growing problem among patients with systemic fungal infections. UV-induced Aspergillus nidulans mutants resistant to terbinafine have been identified, and we report here the characterization of one such gene. A sib-selected, 6.6-kb genomic DNA fragment encodes a salicylate 1-monooxygenase (salA), and a fatty acid synthase subunit (fasC) confers terbinafine resistance upon transformation of a sensitive strain. Subfragments carrying salA but not fasC confer terbinafine resistance. salA is present as a single-copy gene on chromosome VI and encodes a protein of 473 amino acids that is homologous to salicylate 1-monooxygenase, a well-characterized naphthalene-degrading enzyme in bacteria. salA transcript accumulation analysis showed terbinafine-dependent induction in the wild type and the UV-induced mutant Terb7, as well as overexpression in a strain containing the salA subgenomic DNA fragment, probably due to the multicopy effect caused by the transformation event. Additional naphthalene degradation enzyme-coding genes are present in fungal genomes, suggesting that resistance could follow degradation of the naphthalene ring contained in terbinafine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / metabolism
  • Antifungal Agents / pharmacology*
  • Aspergillus nidulans / drug effects*
  • Aspergillus nidulans / enzymology
  • Aspergillus nidulans / genetics
  • Blotting, Northern
  • Blotting, Southern
  • Chromosome Mapping
  • Culture Media
  • DNA Fragmentation / genetics
  • DNA Primers
  • DNA, Fungal / genetics
  • Drug Resistance, Fungal
  • Fatty Acid Synthases / metabolism
  • Gene Library
  • Genes, Fungal / genetics
  • Mixed Function Oxygenases / genetics
  • Mixed Function Oxygenases / physiology*
  • Naphthalenes / metabolism
  • Naphthalenes / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Terbinafine
  • Transcription, Genetic
  • Transformation, Genetic

Substances

  • Antifungal Agents
  • Culture Media
  • DNA Primers
  • DNA, Fungal
  • Naphthalenes
  • Mixed Function Oxygenases
  • salicylate 1-monooxygenase
  • Fatty Acid Synthases
  • Terbinafine