Print Email Facebook Twitter Ionophoric effects of the antitubercular drug bedaquiline Title Ionophoric effects of the antitubercular drug bedaquiline Author Hards, Kiel (University of Otago) McMillan, D.G.G. (TU Delft BT/Biocatalysis) Schurig-Briccio, Lici A. (University of Illinois) Gennis, Robert B. (University of Illinois) Lill, Holger (Vrije Universiteit Amsterdam) Bald, Dirk (Vrije Universiteit Amsterdam) Cook, Gregory M. (University of Otago; The University of Auckland) Date 2018-07-10 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. Subject BedaquilineIonophoreRespirationTuberculosisUncoupler To reference this document use: http://resolver.tudelft.nl/uuid:b1858005-c29f-4c0b-9c5d-85168fe055f4 DOI https://doi.org/10.1073/pnas.1803723115 Embargo date 2019-01-10 ISSN 0027-8424 Source Proceedings of the National Academy of Sciences of the United States of America, 115 (28), 7326-7331 Bibliographical note Accepted Author Manuscript Part of collection Institutional Repository Document type journal article Rights © 2018 Kiel Hards, D.G.G. McMillan, Lici A. Schurig-Briccio, Robert B. Gennis, Holger Lill, Dirk Bald, Gregory M. Cook Files PDF Proof.pdf 1.95 MB Close viewer /islandora/object/uuid:b1858005-c29f-4c0b-9c5d-85168fe055f4/datastream/OBJ/view