Mycobacterium tuberculosis F1Fo ATP synthase subunit c (AtpE)

The Mycobacterium tuberculosis F1Fo ATP synthase subunit c (AtpE) is a vital component of the bacterial energy-generating complex, forming a rotor ring (c-ring) within the Fo sector of the enzyme (Preiss et al., 2015, PNAS). This c-ring facilitates the transport of protons across the plasma membrane, converting the electrochemical gradient into mechanical rotation that drives ATP synthesis in the F1 sector (Koul et al., 2007, Nat. Chem. Biol.). As Mycobacterium tuberculosis is an obligate aerobe that depends on oxidative phosphorylation for survival, the ATP synthase is essential for both actively replicating and dormant bacilli (Andries et al., 2005, Science). The diarylquinoline drug bedaquiline (Sirturo) targets this specific subunit by binding to a conserved pocket, effectively locking the c-ring and preventing the rotation necessary for ATP production (Preiss et al., 2015, PNAS). This inhibition leads to a rapid decline in intracellular ATP levels and subsequent bacterial death, making it a cornerstone in the treatment of multi-drug resistant tuberculosis (MDR-TB) (Mahajan, 2013, Int. J. App. Basic Med. Res.). While highly effective, the use of drugs targeting this site requires monitoring for potential side effects such as QTc interval prolongation and liver toxicity (Cohen, 2013, Science). The high selectivity of bedaquiline for the mycobacterial c-ring over the human mitochondrial counterpart is due to specific sequence differences in the binding pocket, which minimizes off-target effects (Haagsma et al., 2009, Antimicrob. Agents Chemother.).

Other names

ATP synthase subunit cF-type H+-transporting ATPase subunit cc-ringAtpE subunit

Bedaquiline and its analogs bind to the c-subunit of the Fo rotor, physically obstructing the rotation of the c-ring and blocking the proton-pumping mechanism required for ATP synthesis (Andries et al., 2005, Science; Preiss et al., 2015, PNAS).