Mycobacterial F-type ATP synthase (F-ATP synthase)

Mycobacterial F-type ATP synthase is a multi-subunit enzyme complex essential for the survival of Mycobacterium tuberculosis in both replicating and non-replicating (dormant) states [3, 4]. It functions as the final component of the oxidative phosphorylation pathway, utilizing the proton motive force generated by the electron transport chain to synthesize ATP from ADP and inorganic phosphate [6, 11]. The enzyme consists of a membrane-embedded Fo domain and a catalytic F1 domain, with unique structural features such as an extended C-terminus on the alpha subunit and a specific gamma-loop that regulate its latent ATPase activity to prevent energy waste [1, 13]. These mycobacteria-specific elements distinguish it from the human mitochondrial ATP synthase, providing a basis for high drug selectivity [4, 8]. The target is clinically validated by the success of bedaquiline, a diarylquinoline that binds to the c-subunit rotor to inhibit ATP synthesis [5, 7]. Inhibition of this enzyme leads to a lethal depletion of cellular ATP, making it effective against multi-drug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis strains [9, 10]. Beyond bedaquiline, several next-generation inhibitors like TBAJ-587 and TBAJ-876 are in development to improve safety profiles and overcome resistance [5, 11]. However, therapeutic challenges include the risk of QTc prolongation and the emergence of resistance through mutations in the atpE gene [6, 9].

Other names

F1Fo-ATP synthaseATP synthase complexH+-transporting ATP synthaseProton-translocating ATP synthaseMycobacterial F1Fo-ATPase

Inhibition of the c-subunit rotor or proton-conducting channel, leading to the cessation of ATP synthesis and depletion of cellular energy stores.