Mycobacterium tuberculosis F0F1 ATP synthase c-subunit and epsilon-subunit (Mtb F0F1 ATP synthase c/ε)

The Mycobacterium tuberculosis F0F1 ATP synthase c-subunit and epsilon-subunit are essential components of the rotary engine responsible for generating adenosine triphosphate (ATP) in the tuberculosis-causing pathogen [1.1.2, 1.5.1]. The c-subunit, encoded by the atpE gene, forms a membrane-embedded oligomeric ring that facilitates proton translocation across the inner membrane, while the epsilon-subunit, encoded by atpC, serves as a regulatory coupling factor between the rotor and the catalytic F1 domain [1.2.1, 1.3.3]. This complex is vital for the survival of M. tuberculosis in both replicating and non-replicating (dormant) states, as it maintains energy homeostasis under varying environmental conditions [1.1.3, 1.5.2]. The diarylquinoline drug Bedaquiline (Sirturo) specifically targets these subunits, binding to the c-ring to stall its rotation and interacting with the epsilon-subunit to disrupt energy coupling [1.3.1, 1.4.2]. This dual-subunit targeting mechanism leads to a rapid depletion of cellular ATP and subsequent bacterial death [1.1.1, 1.3.3]. Clinical resistance is primarily associated with mutations in the atpE gene that hinder drug binding, and therapeutic challenges include managing drug-induced cardiotoxicity, such as QT interval prolongation [1.3.3, 1.4.2].

Other names

AtpEAtpCATP synthase subunit cATP synthase subunit epsilonF-type ATPase c-subunitF-type ATPase epsilon-subunitMycobacterial F0F1 ATP synthase c/ε complex

Inhibition of ATP synthesis by binding to the c-ring to stall rotation and to the epsilon subunit to block coupling between the rotor and the catalytic headpiece [1.3.3, 1.4.2].