Interpretation of the mechanism of action of antituberculosis drug bedaquiline based on a novel two‐ion theory of energy coupling in ATP synthesis

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 F(O) portion of the F(1)F(O)‐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.