Breaking the barrier: from biosynthetic inhibition to multidimensional modulation of the mycobacterial cell wall in tuberculosis therapy.

Tuberculosis remains a leading cause of global mortality, with the rise of multidrug resistant and extensively drug-resistant Mycobacterium tuberculosis strains highlighting an urgent need for novel therapeutics. The mycobacterial cell wall has long served as a validated drug target, owing to its unique architecture comprising arabinogalactan, peptidoglycan, and mycolic acids. This review provides a comprehensive overview of recent advances in cell wall targeting anti tuberculosis drug discovery, encompassing both established and emerging targets within the major biosynthetic pathways. Beyond conventional enzymatic inhibition, a multidimensional framework is explored that includes disrupting cell wall integrity through alternative mechanisms, interfering with energy metabolism and regulatory networks, blocking the secretion and transport of cell wall components, harnessing host-directed therapies and antimicrobial peptides, and leveraging nanotechnology-based delivery systems. By integrating discoveries across these diverse fronts, this review highlights evolving strategies and offers a forward looking perspective on the development of ultra short, highly effective, and resistance proof tuberculosis regimens.