Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis

J Biol Chem. 2008 Sep 12;283(37):25273-80. doi: 10.1074/jbc.M803899200. Epub 2008 Jul 14.

Abstract

An estimated one-third of the world population is latently infected with Mycobacterium tuberculosis. These nonreplicating, dormant bacilli are tolerant to conventional anti-tuberculosis drugs, such as isoniazid. We recently identified diarylquinoline R207910 (also called TMC207) as an inhibitor of ATP synthase with a remarkable activity against replicating mycobacteria. In the present study, we show that R207910 kills dormant bacilli as effectively as aerobically grown bacilli with the same target specificity. Despite a transcriptional down-regulation of the ATP synthase operon and significantly lower cellular ATP levels, we show that dormant mycobacteria do possess residual ATP synthase enzymatic activity. This activity is blocked by nanomolar concentrations of R207910, thereby further reducing ATP levels and causing a pronounced bactericidal effect. We conclude that this residual ATP synthase activity is indispensable for the survival of dormant mycobacteria, making it a promising drug target to tackle dormant infections. The unique dual bactericidal activity of diarylquinolines on dormant as well as replicating bacterial subpopulations distinguishes them entirely from the current anti-tuberculosis drugs and underlines the potential of R207910 to shorten tuberculosis treatment.

MeSH terms

  • Adenosine Triphosphate / chemistry*
  • Antitubercular Agents / pharmacology
  • Gene Expression Regulation, Bacterial*
  • Homeostasis*
  • Mitochondrial Proton-Translocating ATPases / chemistry
  • Models, Biological
  • Mycobacterium / metabolism*
  • Mycobacterium bovis / drug effects
  • Mycobacterium bovis / metabolism
  • Mycobacterium smegmatis / drug effects
  • Mycobacterium smegmatis / metabolism
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / metabolism
  • Nitric Oxide / chemistry
  • Oxygen / chemistry
  • Quinolines / pharmacology*
  • RNA, Messenger / metabolism
  • Time Factors

Substances

  • Antitubercular Agents
  • Quinolines
  • RNA, Messenger
  • Nitric Oxide
  • Adenosine Triphosphate
  • Mitochondrial Proton-Translocating ATPases
  • Oxygen