Ionophoric Effects of the Antitubercular Drug Bedaquiline

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2018 Jun 27

PMID 29941569

Citations 47

Authors

Kiel Hards

Duncan G G McMillan

Lici A Schurig-Briccio

Robert B Gennis

Holger Lill

Dirk Bald

Gregory M Cook

Affiliations

Soon will be listed here.

Abstract

Bedaquiline (BDQ), an inhibitor of the mycobacterial FF-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 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 F subunit into liposomes enhanced the ionophoric activity of BDQ. We discuss the possibility that localization of BDQ at FF-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.

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