Oxidative phosphorylation pathway of Mycobacterium tuberculosis (OXPHOS pathway)

The oxidative phosphorylation pathway in *Mycobacterium tuberculosis* consists of membrane-bound multi-enzyme complexes that form the electron transport chain (ETC), culminating in ATP synthesis by F\u005C(_1\u005C)F\u005C(_0\u005C)-ATP synthase. Electrons from metabolic substrates are transferred through NADH dehydrogenases and succinate dehydrogenase to menaquinone and then to terminal oxidases (cytochrome bc1-aa3 and cytochrome bd oxidase). This transfer drives proton pumping across the membrane, generating a proton motive force (PMF) that is essential for ATP production and bacterial viability. The pathway is remarkably flexible, allowing rapid rerouting between respiratory complexes under stress conditions (e.g., drug inhibition, hypoxia). Targeting this pathway with drugs such as bedaquiline and Q203 has revolutionized tuberculosis therapy by exploiting its essentiality for energy metabolism and survival, especially in persistent and drug-resistant Mtb strains. These drugs work by disrupting energy production, membrane potential, and redox balance, leading to bacterial death. Clinical challenges include resistance development and safety concerns arising from off-target effects in human host tissues[4][2][7][1][6].

Other names

Energy metabolism pathwayRespiratory chainElectron transport chain (ETC)

Inhibition of ATP synthase (depletes cellular ATP); Inhibition of cytochrome bc1 complex (blocks electron transport, disrupts PMF, ATP synthesis); Disruption of transmembrane proton gradient (interrupts oxidative phosphorylation); Induction of reactive oxygen species (cellular damage/killing)