Difference between revisions of "Hards 2018 Proc Natl Acad Sci U S A"
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|abstract=Bedaquiline (BDQ), an inhibitor of the mycobacterial F<sub>1</sub>F<sub>o</sub>-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<sup>+</sup>/K<sup>+</sup> ionophore, causing transmembrane pH and potassium gradients to be equilibrated. Despite the apparent lack of a BDQ-binding site, incorporating the ''E. coli'' F<sub>o</sub> subunit into liposomes enhanced the ionophoric activity of BDQ. We discuss the possibility that localization of BDQ at F<sub>1</sub>F<sub>o</sub>-ATP synthases enables BDQ to create an uncoupled microenvironment, by antiporting H<sup>+</sup>/K<sup>+</sup> Ionophoric properties may be desirable in high-affinity antimicrobials targeting integral membrane proteins. | |abstract=Bedaquiline (BDQ), an inhibitor of the mycobacterial F<sub>1</sub>F<sub>o</sub>-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<sup>+</sup>/K<sup>+</sup> ionophore, causing transmembrane pH and potassium gradients to be equilibrated. Despite the apparent lack of a BDQ-binding site, incorporating the ''E. coli'' F<sub>o</sub> subunit into liposomes enhanced the ionophoric activity of BDQ. We discuss the possibility that localization of BDQ at F<sub>1</sub>F<sub>o</sub>-ATP synthases enables BDQ to create an uncoupled microenvironment, by antiporting H<sup>+</sup>/K<sup>+</sup> Ionophoric properties may be desirable in high-affinity antimicrobials targeting integral membrane proteins. | ||
|keywords= | |keywords=Bedaquiline, Ionophore, Respiration, Tuberculosis, Uncoupler | ||
|editor=[[Plangger M]], [[Kandolf G]], | |editor=[[Plangger M]], [[Kandolf G]], | ||
}} | }} | ||
Latest revision as of 10:56, 14 August 2018
| Hards K, McMillan DGG, Schurig-Briccio LA, Gennis RB, Lill H, Bald D, Cook GM (2018) Ionophoric effects of the antitubercular drug bedaquiline. Proc Natl Acad Sci U S A 115:7326-31. |
Hards K, McMillan DGG, Schurig-Briccio LA, Gennis RB, Lill H, Bald D, Cook GM (2018) Proc Natl Acad Sci U S A
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 • Bioblast editor: Plangger M, Kandolf G
Labels: MiParea: Respiration, Pharmacology;toxicology
Pathology: Other
Organism: Eubacteria
Preparation: Intact organism
Regulation: ATP production, Ion;substrate transport, Uncoupler
HRR: O2k-Fluorometer
Labels, 2018-08
