A Mycobacterium tuberculosis cytochrome bd oxidase mutant is hypersensitive to bedaquiline

Michael Berney, Travis E. Hartman, William R. Jacobs

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

The new medicinal compound bedaquiline (BDQ) kills Mycobacterium tuberculosis by inhibiting F1Fo-ATP synthase. BDQ is bacteriostatic for 4 to 7 days and kills relatively slowly compared to other frontline tuberculosis (TB) drugs. Here we show that killing with BDQ can be improved significantly by inhibiting cytochrome bd oxidase, a non-proton-pumping terminal oxidase. BDQ was instantly bactericidal against a cytochrome bd oxidase null mutant of M. tuberculosis, and the rate of killing was increased by more than 50%. We propose that this exclusively bacterial enzyme should be a high-priority target for new drug discovery.

IMPORTANCE A major drawback of current TB chemotherapy is its long duration. New drug regimens with rapid killing kinetics are desperately needed. Our study demonstrates that inhibition of a nonessential bacterial enzyme greatly improves the efficacy of the latest TB drug bedaquiline and emphasizes that screening for compounds with synergistic killing mechanisms is a promising strategy.

Original languageEnglish (US)
Article numbere01275-14
JournalmBio
Volume5
Issue number4
DOIs
StatePublished - Jul 15 2014

ASJC Scopus subject areas

  • Microbiology
  • Virology

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