Exploiting key metabolic pathways of Mycobacterium tuberculosis for next-generation anti-tubercular drug discovery

Mycobacterium tuberculosis (Mtb) caused disease Tuberculosis (TB) continues to be one of the leading causes of mortality although decades of medical research has progressed. With the alarming rise in multidrug-resistant and extensively drug-resistant strains, the effectiveness of conventional therapeutic regimens is being severely compromised. This mounting resistance not only diminishes the clinical success of existing drugs but also poses a significant health threat, underscoring the urgent need to develop innovative therapeutic strategies that can overcome resistance mechanisms and restore treatment efficacy. Recent research has revealed that Mtb relies on unique metabolic adaptations for its survival and persistence within the host, particularly through the shikimate pathway, the methylcitrate cycle and the glyoxylate shunt. These pathways enable the bacterium to synthesize essential metabolites, detoxify toxic intermediates and conserve carbon skeletons under nutrient deficient conditions. The enzymes involved in these pathways exhibit distinct structural and functional features that are absent in humans, making them highly selective as drug targets. Advances in structural biology, enzyme kinetics and computational approaches have facilitated the discovery of promising inhibitors derived from natural products, synthetic scaffolds and fragment-based designs. This review discusses the mechanistic insights, regulatory roles and inhibitor development efforts targeting key enzymes from these three metabolic pathways. By integrating biochemical, structural and medicinal chemistry perspectives, here in the potential of these metabolic nodes as underexploited yet powerful avenues for next-generation anti-tubercular drug discovery are reviewed.