Respiratory flexibility in response to inhibition of cytochrome C oxidase in Mycobacterium tuberculosis

Antimicrob Agents Chemother. 2014 Nov;58(11):6962-5. doi: 10.1128/AAC.03486-14. Epub 2014 Aug 25.

Abstract

We report here a series of five chemically diverse scaffolds that have in vitro activities on replicating and hypoxic nonreplicating bacilli by targeting the respiratory bc1 complex in Mycobacterium tuberculosis in a strain-dependent manner. Deletion of the cytochrome bd oxidase generated a hypersusceptible mutant in which resistance was acquired by a mutation in qcrB. These results highlight the promiscuity of the bc1 complex and the risk of targeting energy metabolism with new drugs.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Antitubercular Agents / pharmacology*
  • Binding Sites
  • Drug Resistance, Multiple, Bacterial / genetics*
  • Electron Transport / drug effects
  • Electron Transport Complex IV / antagonists & inhibitors*
  • Electron Transport Complex IV / genetics
  • Energy Metabolism / drug effects
  • Gene Knockout Techniques
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Mycobacterium tuberculosis / genetics
  • Oxazines / chemistry
  • Protein Structure, Tertiary
  • Pyridines / pharmacology
  • Tuberculosis / drug therapy*
  • Xanthenes / chemistry

Substances

  • Antitubercular Agents
  • Oxazines
  • Pyridines
  • Xanthenes
  • resazurin
  • Electron Transport Complex IV
  • imidazo(1,2-a)pyridine

Associated data

  • PDB/1NTM
  • PDB/1ZRT
  • PDB/2QJP
  • PDB/3CX5
  • PDB/3H1H