Tuberculosis (TB) claims the lives of 1.3 million people each year, more than any other bacterial infection. Hence great interest was generated in health communities upon the recent introduction of the new diarylquinoline anti-TB drug, bedaquiline. Bedaquiline acts by binding to the c-subunit in the membrane-bound FO portion of the F1FO-adenosine triphosphate (ATP) synthase, the universal enzyme that produces the ATP needed by cells. However, the mechanism of killing by bedaquiline is not fully understood. Recent observations related to the bactericidal effects of bedaquiline, which show that it is a potent uncoupler of respiration-driven ATP synthesis in Mycobacterium smegmatis are summarized. These observations are then interpreted from the standpoint of Nath's two-ion theory of energy coupling in ATP synthesis (Nath, Biophys. Chem. 2017; 230:45-52). Especial importance is given to the interpretation of biochemical fluorescence quenching data, and the differences between the uncoupling induced by bedaquiline from that by the classical anionic uncouplers of oxidative phosphorylation are highlighted. Suggestions for new experiments that could lead to a better understanding of the uncoupling mechanism are made. A model of uncoupling action by the drug is presented, and the biochemical basis underlying uncoupling of ATP synthesis and lethality in mycobacteria is elucidated. The major biological implications arising from these novel insights are discussed. It is hoped that the analysis will lead to a more fundamental understanding of biological energy coupling, uncoupling and transduction, and to an integrated view for the design of novel antimicrobials by future research in the field.

中文翻译：

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基于ATP合成能量耦合的新型双离子理论解释抗结核药物贝达喹啉的作用机制。

结核病 (TB) 每年夺去 130 万人的生命，比任何其他细菌感染都要多。因此，最近推出新的二芳基喹啉抗结核药物贝达喹啉后，引起了卫生界的极大兴趣。贝达喹啉通过与 F1FO-三磷酸腺苷 (ATP) 合酶 (ATP) 膜结合 FO 部分的 c 亚基结合发挥作用，ATP 合酶是产生细胞所需 ATP 的通用酶。然而，贝达喹啉的杀伤机制尚不完全清楚。总结了最近与贝达喹啉杀菌作用相关的观察结果，表明它是耻垢分枝杆菌中呼吸驱动的 ATP 合成的有效解偶联剂。然后从 Nath ATP 合成中能量耦合的双离子理论的角度解释这些观察结果 (Nath, Biophys. Chem. 2017; 230:45-52)。特别重要的是生化荧光猝灭数据的解释，并强调了贝达喹啉诱导的解偶联与氧化磷酸化的经典阴离子解偶联剂之间的差异。提出了新实验的建议，以更好地理解解偶联机制。提出了药物解偶联作用的模型，并阐明了分枝杆菌中 ATP 合成和致死性解偶联的生化基础。讨论了这些新见解所产生的主要生物学意义。希望该分析能够使人们对生物能量耦合、解偶联和转导有更基本的理解，并通过该领域的未来研究对新型抗菌药物的设计产生综合的看法。