Combination strategies targeting multiple ETC subunits as a rational approach for drug-resistant TB therapy

Regardless of the environment, Mycobacterium tuberculosis (Mtb) relies on oxidative phosphorylation as a critical metabolic process. Because the mammalian genome lacks the NADH dehydrogenase type II (NDH-2), which serves as the entry point for electrons into the oxidative phosphorylation (Ox-Phos) pathway, can be a potential target in combating the infection. With the ability to decrease the period of treatment medication, new families of antibiotics that interfere with oxidative phosphorylation pathway components are particularly effective in treating latent or dormant mycobacterial infections. Consequently, it may be possible to effectively treat the infection by targeting NDH-2, which is important in the synthesis of respiratory ATP. Here, the bioenergetics of Mtb and the role of NDH-2 in the production of ATP are discussed. NDH-2 is a crucial enzyme for the generation of ATP and inhibitors can be targeted against both drug-resistant and drug-susceptible Mtb. Interestingly, under nutrient-starved and hypoxic conditions, NDH-2 expression is upregulated to sustain the energy requirements of Mtb. This adaptive regulation highlights that NDH-2 remains functionally essential even in non-replicating states, thereby supporting its validity as a robust therapeutic target. Other Electron transport chain (ETC) inhibitors like bedaquiline (BDQ) can be used in order to tackle the emergence of resistance and will be helpful in shortening the course of treatment therapy. In order to combat drug-resistant and drug-susceptible Mycobacterium tuberculosis, targeting NDH-2 and other components of the oxidative phosphorylation pathway, offers a promising approach that can effectively shorten treatment duration and address latent infections.