Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2018 Jul 10;115(28):7326-7331. doi: 10.1073/pnas.1803723115. Epub 2018 Jun 25.

Ionophoric effects of the antitubercular drug bedaquiline.

Author information

1
Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, 9054 Dunedin, New Zealand.
2
Department of Biotechnology, Delft University of Technology, 2629 HZ Delft, The Netherlands.
3
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
4
Department of Molecular Cell Biology, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
5
Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, 9054 Dunedin, New Zealand; gregory.cook@otago.ac.nz.
6
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, 1042 Auckland, New Zealand.

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 antiporting H+/K+ Ionophoric properties may be desirable in high-affinity antimicrobials targeting integral membrane proteins.

KEYWORDS:

bedaquiline; ionophore; respiration; tuberculosis; uncoupler

PMID:
29941569
PMCID:
PMC6048524
DOI:
10.1073/pnas.1803723115
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center