TY - JOUR
T1 - Ionophoric effects of the antitubercular drug bedaquiline
AU - Hards, Kiel
AU - McMillan, Duncan G.G.
AU - Schurig-Briccio, Lici A.
AU - Gennis, Robert B.
AU - Lill, Holger
AU - Bald, Dirk
AU - Cook, Gregory M.
N1 - Accepted Author Manuscript
PY - 2018/7/10
Y1 - 2018/7/10
N2 - 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.
AB - 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.
KW - Bedaquiline
KW - Ionophore
KW - Respiration
KW - Tuberculosis
KW - Uncoupler
UR - http://www.scopus.com/inward/record.url?scp=85049625033&partnerID=8YFLogxK
UR - http://resolver.tudelft.nl/uuid:b1858005-c29f-4c0b-9c5d-85168fe055f4
U2 - 10.1073/pnas.1803723115
DO - 10.1073/pnas.1803723115
M3 - Article
AN - SCOPUS:85049625033
SN - 0027-8424
VL - 115
SP - 7326
EP - 7331
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 28
ER -