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Ionophoric effects of the antitubercular drug bedaquiline.

Hards, Kiel; McMillan, Duncan G G; Schurig-Briccio, Lici A; Gennis, Robert B; Lill, Holger; Bald, Dirk; Cook, Gregory M.
Proc Natl Acad Sci U S A; 115(28): 7326-7331, 2018 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-29941569
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.
Selo DaSilva