Ionophoric effects of the antitubercular drug bedaquiline

Kiel Hards, Duncan G.G. McMillan, Lici A. Schurig-Briccio, Robert B. Gennis, Holger Lill, Dirk Bald, Gregory M. Cook

Research output: Contribution to journalArticle

Abstract

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 antiport-ing H+/K+. Ionophoric properties may be desirable in high-affinity antimicrobials targeting integral membrane proteins.

Original languageEnglish (US)
Pages (from-to)7326-7331
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number28
DOIs
StatePublished - Jul 10 2018

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Keywords

  • Bedaquiline
  • Ionophore
  • Respiration
  • Tuberculosis
  • Uncoupler

ASJC Scopus subject areas

  • General

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