Mutations in Saccharomyces cerevisiae sterol C5-desaturase conferring resistance to the CYP51 inhibitor fluconazole

Colin J. Jackson, David Christopher Lamb, Nigel J. Manning, Diane Elizabeth Kelly, Steven Lewis Kelly

Research output: Contribution to journalArticlepeer-review

19 Citations (SciVal)

Abstract

Understanding fluconazole resistance is important as it emerged as a serious clinical problem for this CYP51, sterol 14α-demethylase, inhibitor. One mechanism, observed first in Saccharomyces cerevisiae, was through defective sterol C5-desaturase (Erg3p) required to form the fungistatic sterol end-product resulting from CYP51 inhibition, 14α-methylergosta-8,24(28)-dien-3β,6α-diol. Here, we report molecular changes resulting in both blocked mutants and also leaky mutants in which reduced ergosterol levels were detected. Blocked mutants exhibited nonsense and frameshift mutations, while leaky mutants contained missense mutations that were generally in conserved positions based on the alignment of sterol C5-desaturases and located mainly between residues 250 and 282.
Original languageEnglish
Pages (from-to)999-1004
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume309
Issue number4
Early online date06 Sept 2003
DOIs
Publication statusPublished - 03 Oct 2003

Keywords

  • Sterol C5-desaturase
  • Cytochrome P450 inhibition
  • Fluconazole
  • Antifungal resistance
  • Mutation

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