Ionophoric effects of the antitubercular drug bedaquiline.

Abstract

Bedaquiline (BDQ), an inhibitor of the mycobacterial F₁F_o-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 <i>Escherichia coli</i> 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 <i>E. coli</i> F_o subunit into liposomes enhanced the ionophoric activity of BDQ. We discuss the possibility that localization of BDQ at F₁F_o-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.