Molecular Mechanism of Terbinafine Resistance in Saccharomyces cerevisiae

  • Leber R
  • Fuchsbichler S
  • Klobučníková V
 et al. 
  • 33

    Readers

    Mendeley users who have this article in their library.
  • 32

    Citations

    Citations of this article.

Abstract

Ten mutants of the yeast Saccharomyces cerevisiae resistant to the antimycotic terbinafine were isolated after chemical or UV mutagenesis. Molecular analysis of these mutants revealed single base pair exchanges in the ERG1 gene coding for squalene epoxidase, the target of terbinafine. The mutants did not show cross-resistance to any of the substrates of various pleiotropic drug resistance efflux pumps tested. The ERG1 mRNA levels in the mutants did not differ from those in the wild-type parent strains. Terbinafine resistance was transmitted with the mutated alleles in gene replacement experiments, proving that single amino acid substitutions in the Erg1 protein were sufficient to confer the resistance phenotype. The amino acid changes caused by the point mutations were clustered in two regions of the Erg1 protein. Seven mutants carried the amino acid substitu- tions F402L (one mutant), and P430S (five mutants in the C-terminal part of the protein; and three mutants carried an L251F exchange in the central part of the protein. Interestingly, all exchanges indentified involved amino acids which are conserved in the squalene epoxidases of yeasts and mammals. Two mutations that were generated by PCR mutagenesis of the ERG1 gene and that conferred terbinafine resistance mapped in the same regions of the Erg1 protein, with one resulting in an L251F exchange and the other resulting in an F433S exchange. The results strongly indicate that these regions are responsible for the interaction of yeast squalene epoxidase with terbinafine

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document

Get full text

Authors

  • Regina Leber

  • Sandra Fuchsbichler

  • Vlasta Klobučníková

  • Natascha Schweighofer

  • Eva Pitters

  • Kathrin Wohlfarter

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free