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 JournalArticleAcademicpeer-review

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
Pages (from-to)7326-7331
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number28
Early online date25 Jun 2018
DOIs
Publication statusPublished - 10 Jul 2018

Fingerprint

bedaquiline
Antitubercular Agents
Adenosine Triphosphate
Escherichia coli
Proton-Motive Force
Ionophores
Ion Transport
Drug Discovery
Liposomes
Energy Metabolism
Potassium
Membrane Proteins
Cell Death

Keywords

  • Bedaquiline
  • Ionophore
  • Respiration
  • Tuberculosis
  • Uncoupler

Cite this

Hards, Kiel ; McMillan, Duncan G.G. ; Schurig-Briccio, Lici A. ; Gennis, Robert B. ; Lill, Holger ; Bald, Dirk ; Cook, Gregory M. / Ionophoric effects of the antitubercular drug bedaquiline. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 28. pp. 7326-7331.
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Ionophoric effects of the antitubercular drug bedaquiline. / Hards, Kiel; McMillan, Duncan G.G.; Schurig-Briccio, Lici A.; Gennis, Robert B.; Lill, Holger; Bald, Dirk; Cook, Gregory M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 28, 10.07.2018, p. 7326-7331.

Research output: Contribution to JournalArticleAcademicpeer-review

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