Turning the respiratory flexibility of Mycobacterium tuberculosis against itself

Nat Commun. 2016 Aug 10;7:12393. doi: 10.1038/ncomms12393.

Abstract

The Mycobacterium tuberculosis (Mtb) electron transport chain (ETC) has received significant attention as a drug target, however its vulnerability may be affected by its flexibility in response to disruption. Here we determine the effect of the ETC inhibitors bedaquiline, Q203 and clofazimine on the Mtb ETC, and the value of the ETC as a drug target, by measuring Mtb's respiration using extracellular flux technology. We find that Mtb's ETC rapidly reroutes around inhibition by these drugs and increases total respiration to maintain ATP levels. Rerouting is possible because Mtb rapidly switches between terminal oxidases, and, unlike eukaryotes, is not susceptible to back pressure. Increased ETC activity potentiates clofazimine's production of reactive oxygen species, causing rapid killing in vitro and in a macrophage model. Our results indicate that combination therapy targeting the ETC can be exploited to enhance killing of Mtb.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / therapeutic use
  • Clofazimine / pharmacology
  • Clofazimine / therapeutic use
  • Diarylquinolines / pharmacology
  • Diarylquinolines / therapeutic use
  • Drug Therapy, Combination / methods
  • Electron Transport Chain Complex Proteins / antagonists & inhibitors*
  • Hep G2 Cells
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Inhibitory Concentration 50
  • Macrophages / microbiology
  • Mice
  • Mutation
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / physiology*
  • Piperidines / chemical synthesis
  • Piperidines / pharmacology
  • Piperidines / therapeutic use
  • Pyridines / chemical synthesis
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • RAW 264.7 Cells
  • Reactive Oxygen Species / metabolism*
  • Tuberculosis, Multidrug-Resistant / drug therapy*
  • Tuberculosis, Multidrug-Resistant / microbiology

Substances

  • Antitubercular Agents
  • Diarylquinolines
  • Electron Transport Chain Complex Proteins
  • Imidazoles
  • Piperidines
  • Pyridines
  • Reactive Oxygen Species
  • telacebec
  • bedaquiline
  • Adenosine Triphosphate
  • Clofazimine