Recent Developments in Structurally Diverse Anti-Tubercular Drug Molecules and Their Molecular Targets Against Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb), the primary etiological agent of tuberculosis (TB), remains a major global health threat. In recent years, Mtb strains exhibiting complete drug resistance have emerged, evolving unique mechanisms to survive within the host. Although multidrug therapy was introduced four decades ago, the rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains necessitates the urgent development of novel therapeutic targets and interventions. Current drug development efforts have been insufficient to curb the TB epidemic, with anti-TB drug discovery largely stagnant for nearly half a century. However, in the past decade, three promising drugs—delamanid, bedaquiline, and pretomanid—have unexpectedly emerged. Furthermore, numerous modified compounds, initially developed to combat other infections, have demonstrated potential anti-TB activity. These drugs exhibit diverse targets and mechanisms of action, including the inhibition of cell wall biosynthesis, DNA/RNA synthesis, protein synthesis, and metabolic pathways. This article reviews the molecular targets, mechanisms of action, drug interactions, and structure–activity relationships (SAR) of newly approved and repurposed drugs for TB treatment. While TB poses a global burden, its impact is disproportionately felt in developing countries, where latent Mtb infection is estimated to affect nearly one-third of the population. Although TB is curable, treatment becomes significantly more challenging with progression to MDR and even more so with XDR forms. Despite decades of stagnation, recent breakthroughs—including the discovery of delamanid and bedaquiline and the repurposing of drugs like linezolid and clofazimine—offer renewed hope for effective TB management.