Targeting type II NADH dehydrogenase in tuberculosis treatment: A review

Tuberculosis (TB), a critical global health issue, continues to impose significant harm on human populations worldwide, and the increasing prevalence of drug-resistant TB strains has exacerbated the challenges in effective treatment, underscoring an urgent need for the development of new therapeutic agents with innovative mechanisms of action. The introduction of bedaquiline highlights targeting Mycobacterium tuberculosis (Mtb) energy metabolism as a novel anti-TB strategy. Among the various targets within Mtb's metabolic pathways, type II NADH dehydrogenase (NDH-2) is of particular significance due to its critical function in bacterial respiration and its absence from human cells, rendering it an appealing candidate for selective inhibition. Recent advances have led to the identification of numerous NDH-2 inhibitors, some of which exhibit potent antibacterial activity at nanomolar concentrations, demonstrating their potential as lead compounds for future drug development. This review explores the biochemical function and molecular structure of NDH-2, underscoring its potential as a target for anti-TB therapies. It also discusses the progress made in discovering and optimizing NDH-2 inhibitors, offering insights into their mechanisms of action, efficacy, and pharmacological properties, with the aim of providing an overview that could inform and guide future research efforts towards developing more effective treatments against TB.