Mycobacterium tuberculosis F-ATP synthase (Mtb ATP synthase)

Mycobacterium tuberculosis F-ATP synthase is an essential, multi-subunit enzyme complex that generates cellular ATP from ADP and inorganic phosphate by utilizing the proton motive force across the bacterial membrane [1, 2]. It consists of a soluble F1 region and a membrane-embedded FO region, which together function as a rotary motor [2, 3]. This enzyme is indispensable for the viability of Mycobacterium tuberculosis in both actively replicating and dormant states, as it maintains ATP/ADP homeostasis and the proton motive force required for survival under hostile conditions [1, 3, 11]. In clinical practice, this enzyme is a validated therapeutic target for treating multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis [1, 7, 12]. The diarylquinoline drug bedaquiline (Sirturo) specifically inhibits the mycobacterial F-ATP synthase by binding to the c-ring of the FO domain, thereby stalling enzyme rotation and preventing proton translocation [1, 8, 9]. This inhibition leads to a depletion of intracellular ATP and eventual bacterial death [1, 8, 13]. While the drug is highly selective for the mycobacterial enzyme, safety concerns such as QT prolongation and an increased risk of mortality have been noted, and the emergence of resistance through mutations in the atpE gene remains a therapeutic challenge [1, 7, 8].

Other names

Mtb ATP synthaseF1FO-ATP synthaseBacterial Proton-Translocating ATPaseATP synthase enzyme of Mycobacterium tuberculosis

Inhibition of ATP synthesis by binding to the c-ring of the FO domain, which blocks proton translocation and enzyme rotation [1, 8, 9].