Bacteria can produce ATP by substrate-level phosphorylation of fermentable carbon sources or by oxidative phosphorylation using the electron transport chain and ATP synthase. Some bacteria cannot acquire enough energy through substrate-level phosphorylation and need oxidative phosphorylation for growth. Oligomycins are macrolide antibiotics that inhibit oxidative phosphorylation in mitochondria by inhibiting ATP synthesis. They form a complex with the oligomycin-sensitivity-conferring protein, which decouples the F0 and F1 portions of the ATP synthase complex and interferes with proton transfer through the inner mitochondria membrane (Figure 1). These actions are highly cytotoxic, so are mostly harnessed as biological probes to study oxidative phosphorylation and various mitochondrial processes. Nevertheless, because the ATP synthase plays a crucial role in bacterial growth and metabolism, highly selective inhibitors such as the diarylquinoline TMC207, which targets only the mycobacterial ATP synthase, have been developed to treat drug-resistant M. tuberculosis. Clofazimine targets the type II NADH dehydrogenase (NDH-2), the point of entry of electrons into the respiratory chain of mycobacteria. Further down the chain, pyrazinamide disrupts the proton motive force in mycobacteria.
Figure 1: Antibiotics target various stages of oxidative phosphorylation in mycobacteria.