Bedaquiline Targets the ε Subunit of Mycobacterial F-ATP Synthase

Antimicrob Agents Chemother. 2016 Oct 21;60(11):6977-6979. doi: 10.1128/AAC.01291-16. Print 2016 Nov.

Abstract

The tuberculosis drug bedaquiline inhibits mycobacterial F-ATP synthase by binding to its c subunit. Using the purified ε subunit of the synthase and spectroscopy, we previously demonstrated that the drug interacts with this protein near its unique tryptophan residue. Here, we show that replacement of ε's tryptophan with alanine resulted in bedaquiline hypersusceptibility of the bacteria. Overexpression of the wild-type ε subunit caused resistance. These results suggest that the drug also targets the ε subunit.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / antagonists & inhibitors*
  • Adenosine Triphosphatases / genetics*
  • Alanine / genetics
  • Amino Acid Substitution
  • Antitubercular Agents / pharmacology*
  • Diarylquinolines / pharmacology*
  • Enzyme Inhibitors / pharmacology*
  • Microbial Sensitivity Tests
  • Molecular Targeted Therapy / methods
  • Mycobacterium smegmatis / drug effects
  • Mycobacterium smegmatis / genetics
  • Protein Subunits
  • Tryptophan / genetics

Substances

  • Antitubercular Agents
  • Diarylquinolines
  • Enzyme Inhibitors
  • Protein Subunits
  • bedaquiline
  • Tryptophan
  • Adenosine Triphosphatases
  • Alanine