Journal Article

Ionophoric effects of the antitubercular drug bedaquiline

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

2018

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Adenosine Triphosphate - biosynthesis / Antimicrobial agents / Antitubercular Agents - pharmacology / ATP synthase / Binding sites / Biochemistry / Biological Sciences / Cell death / Diarylquinolines - pharmacology / Drug development / Drug discovery / E coli / Effects / Energy / Energy metabolism / Escherichia coli - metabolism / Escherichia coli Proteins - metabolism / Hydrogen / Hydrogen-Ion Concentration / Ionophores - pharmacology / Liposomes / Localization / Membrane proteins / Metabolism / Potassium / Prescription drugs / Proteins / Proton-Translocating ATPases - metabolism