The cytochrome bd-type quinol oxidase is important for survival of Mycobacterium smegmatis under peroxide and antibiotic-induced stress

Sci Rep. 2015 May 27;5:10333. doi: 10.1038/srep10333.

Abstract

Targeting respiration and ATP synthesis has received strong interest as a new strategy for combatting drug-resistant Mycobacterium tuberculosis. Mycobacteria employ a respiratory chain terminating with two branches. One of the branches includes a cytochrome bc1 complex and an aa3-type cytochrome c oxidase while the other branch terminates with a cytochrome bd-type quinol oxidase. In this communication we show that genetic inactivation of cytochrome bd, but not of cytochrome bc1, enhances the susceptibility of Mycobacterium smegmatis to hydrogen peroxide and antibiotic-induced stress. The type-II NADH dehydrogenase effector clofazimine and the ATP synthase inhibitor bedaquiline were bacteriostatic against wild-type M. smegmatis, but strongly bactericidal against a cytochrome bd mutant. We also demonstrated that the quinone-analog aurachin D inhibited mycobacterial cytochrome bd at sub-micromolar concentrations. Our results identify cytochrome bd as a key survival factor in M. smegmatis during antibiotic stress. Targeting the cytochrome bd respiratory branch therefore appears to be a promising strategy that may enhance the bactericidal activity of existing tuberculosis drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Synthetase Complexes / antagonists & inhibitors
  • ATP Synthetase Complexes / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Clofazimine / pharmacology
  • Diarylquinolines / pharmacology
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism*
  • Gene Knockout Techniques
  • Hydrogen Peroxide / toxicity*
  • Mutation
  • Mycobacterium smegmatis / drug effects*
  • Mycobacterium smegmatis / enzymology
  • NADH Dehydrogenase / chemistry
  • NADH Dehydrogenase / metabolism
  • Quinolones / pharmacology
  • Reactive Oxygen Species / metabolism
  • Stress, Physiological

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Diarylquinolines
  • Quinolones
  • Reactive Oxygen Species
  • aurachin D
  • bedaquiline
  • Hydrogen Peroxide
  • Clofazimine
  • NADH Dehydrogenase
  • Electron Transport Complex IV
  • ATP Synthetase Complexes