Ionophoric effects of the antitubercular drug bedaquiline

Proc Natl Acad Sci U S A. 2018 Jul 10;115(28):7326-7331. doi: 10.1073/pnas.1803723115. Epub 2018 Jun 25.


Bedaquiline (BDQ), an inhibitor of the mycobacterial F1Fo-ATP synthase, has revolutionized the antitubercular drug discovery program by defining energy metabolism as a potent new target space. Several studies have recently suggested that BDQ ultimately causes mycobacterial cell death through a phenomenon known as uncoupling. The biochemical basis underlying this, in BDQ, is unresolved and may represent a new pathway to the development of effective therapeutics. In this communication, we demonstrate that BDQ can inhibit ATP synthesis in Escherichia coli by functioning as a H+/K+ ionophore, causing transmembrane pH and potassium gradients to be equilibrated. Despite the apparent lack of a BDQ-binding site, incorporating the E. coli Fo subunit into liposomes enhanced the ionophoric activity of BDQ. We discuss the possibility that localization of BDQ at F1Fo-ATP synthases enables BDQ to create an uncoupled microenvironment, by antiporting H+/K+ Ionophoric properties may be desirable in high-affinity antimicrobials targeting integral membrane proteins.

Keywords: bedaquiline; ionophore; respiration; tuberculosis; uncoupler.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis*
  • Antitubercular Agents / pharmacology*
  • Diarylquinolines / pharmacology*
  • Escherichia coli / metabolism*
  • Escherichia coli Proteins / metabolism*
  • Hydrogen-Ion Concentration
  • Ionophores / pharmacology*
  • Proton-Translocating ATPases / metabolism*


  • Antitubercular Agents
  • Diarylquinolines
  • Escherichia coli Proteins
  • Ionophores
  • bedaquiline
  • Adenosine Triphosphate
  • Proton-Translocating ATPases