TBAJ-876 Retains Bedaquiline's Activity against Subunits c and ε of Mycobacterium tuberculosis F-ATP Synthase.

ABSTRACT: The antituberculosis drug bedaquiline (BDQ) inhibits Mycobacterium tuberculosis F-ATP synthase by interfering with two subunits. Drug binding to the c subunit stalls the rotation of the c ring, while binding to the ε subunit blocks coupling of c ring rotation to ATP synthesis at the catalytic α₃:β₃ headpiece. BDQ is used for the treatment of drug-resistant tuberculosis. However, the drug is highly lipophilic, displays a long terminal half-life, and has a cardiotoxicity liability by causing QT interval prolongation. Recent medicinal chemistry campaigns have resulted in the discovery of 3,5-dialkoxypyridine analogues of BDQ that are less lipophilic, have higher clearance, and display lower cardiotoxic potential. TBAJ-876, which is a new developmental compound of

SUBMITTER: Sarathy JP 

PROVIDER: S-EPMC6761534 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature