Inhibition of M. tuberculosis and human ATP synthase by BDQ and TBAJ-587

Yuying Zhang, Yuezheng Lai, Shan Zhou, Ting Ran, Yue Zhang, Ziqing Zhao, Ziyan Feng, Long Yu, Jinxu Xu, Kun Shi, Jianyun Wang, Yu Pang, Liang Li, Hongming Chen, Luke W. Guddat, Yan Gao (), Fengjiang Liu (), Zihe Rao () and Hongri Gong ()
Additional contact information
Yuying Zhang: Nankai University
Yuezheng Lai: Nankai University
Shan Zhou: Nankai University
Ting Ran: Guangzhou National Laboratory
Yue Zhang: Nankai University
Ziqing Zhao: Nankai University
Ziyan Feng: Nankai University
Long Yu: Nankai University
Jinxu Xu: Nankai University
Kun Shi: Nankai University
Jianyun Wang: Nankai University
Yu Pang: Capital Medical University
Liang Li: Capital Medical University
Hongming Chen: Guangzhou National Laboratory
Luke W. Guddat: University of Queensland
Yan Gao: ShanghaiTech University
Fengjiang Liu: Guangzhou National Laboratory
Zihe Rao: Nankai University
Hongri Gong: Nankai University

Nature, 2024, vol. 631, issue 8020, 409-414

Abstract: Abstract Bedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase1,2. However, BDQ also inhibits human ATP synthase3. At present, how these compounds interact with either M. tuberculosis ATP synthase or human ATP synthase is unclear. Here we present cryogenic electron microscopy structures of M. tuberculosis ATP synthase with and without BDQ and TBAJ-587 bound, and human ATP synthase bound to BDQ. The two inhibitors interact with subunit a and the c-ring at the leading site, c-only sites and lagging site in M. tuberculosis ATP synthase, showing that BDQ and TBAJ-587 have similar modes of action. The quinolinyl and dimethylamino units of the compounds make extensive contacts with the protein. The structure of human ATP synthase in complex with BDQ reveals that the BDQ-binding site is similar to that observed for the leading site in M. tuberculosis ATP synthase, and that the quinolinyl unit also interacts extensively with the human enzyme. This study will improve researchers’ understanding of the similarities and differences between human ATP synthase and M. tuberculosis ATP synthase in terms of the mode of BDQ binding, and will allow the rational design of novel diarylquinolines as anti-tuberculosis drugs.

Date: 2024
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DOI: 10.1038/s41586-024-07605-8

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