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

被引:56
作者
Sarathy, Jickky Palmae [1 ]
Ragunathan, Priya [2 ]
Shin, Joon [2 ]
Cooper, Christopher B. [3 ]
Upton, Anna M. [3 ]
Gruber, Gerhard [2 ]
Dick, Thomas [4 ,5 ]
机构
[1] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore
[2] Nanyang Technol Univ, Sch Biol Sci, Singapore, Singapore
[3] TB Alliance, Global Alliance TB Drug Dev, New York, NY USA
[4] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Microbiol & Immunol, Singapore, Singapore
[5] Hackensack Meridian Hlth, Ctr Discovery & Innovat, Nutley, NJ 07110 USA
基金
英国医学研究理事会; 美国国家卫生研究院; 新加坡国家研究基金会;
关键词
epsilon subunit; F-ATP synthase; TBAJ-876; bedaquiline; c subunit; diarylquinoline; ADENOSINE-TRIPHOSPHATASE; DRUG BEDAQUILINE; DIARYLQUINOLINES; ANALOGS; IDENTIFICATION; RESISTANCE; MECHANISM; SYSTEM;
D O I
10.1128/AAC.01191-19
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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 epsilon subunit blocks coupling of c ring rotation to ATP synthesis at the catalytic alpha(3):beta(3) 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 this series, shows attractive antitubercular activity and efficacy in a murine tuberculosis model. Here, we asked whether TBAJ-876 and selected analogues of the compound retain BDQ's mechanism of action. Biochemical assays showed that TBAJ-876 is a potent inhibitor of mycobacterial F-ATP synthase. Selection of spontaneous TBAJ-876-resistant mutants identified missense mutations at BDQ's binding site on the epsilon subunit, suggesting that TBAJ-876 retains BDQ's targeting of the c ring. Susceptibility testing against a strain overexpressing the epsilon subunit and a strain harboring an engineered mutation in BDQ's epsilon subunit binding site suggest that TBAJ-876 retains BDQ's activity on the epsilon subunit. Nuclear magnetic resonance (NMR) titration studies confirmed that TBAJ-876 binds to the epsilon subunit at BDQ's binding site. We show that TBAJ-876 retains BDQ's antimycobacterial mode of action. The developmental compound inhibits the mycobacterial F-ATP synthase via a dual-subunit mechanism of interfering with the functions of both the enzyme's c and epsilon subunits.
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页数:11
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