Azole antifungals are potent inhibitors of cytochrome P450 mono-oxygenases and bacterial growth in mycobacteria and streptomycetes

KJ McLean, Ker R Marshall, A Richmond, Iain S Hunter, Kay Fowler, Tobias Kieser, Sudagar S Gurcha, Gurydal S Besra, Andrew W Munro*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

154 Citations (Scopus)

Abstract

The genome sequence of Mycobacterium tuberculosis has revealed the presence of 20 different cytochrome P450 mono-oxygenases (P450s) within this organism, and subsequent genome sequences of other mycobacteria and of Streptomyces coelicolor have indicated that these actinomycetes also have large complements of P450s, pointing to important physiological roles for these enzymes. The actinomycete P450s include homologues of 14alpha-sterol demethylases, the targets for the azole class of drugs in yeast and fungi. Previously, this type of P450 was considered to be absent from bacteria. When present at low concentrations in growth medium, azole antifungal drugs were shown to be potent inhibitors of the growth of Mycobacterium smegmatis and of Streptomyces strains, indicating that one or more of the P450s in these bacteria were viable drug targets. The drugs econazole and clotrimazole were most effective against M. smegmatis (MIC values of

Original languageEnglish
Pages (from-to)2937-2949
Number of pages13
JournalMicrobiology
Volume148
Issue number10
DOIs
Publication statusPublished - Oct 2002

Keywords

  • tuberculosis
  • azole drugs
  • CYP121
  • P450 inhibitors
  • COMPLETE GENOME SEQUENCE
  • STEROL 14-DEMETHYLASE P450
  • DRUG-RESISTANCE
  • ACTIVE-SITE
  • TUBERCULOSIS
  • CYP51
  • 14-ALPHA-DEMETHYLASE
  • DERIVATIVES
  • MECHANISMS
  • SMEGMATIS

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