Review outlines multidimensional strategies to overcome drug-resistant tuberculosis by targeting the mycobacterial cell wall

Tuberculosis (TB) remains a leading cause of global mortality, exacerbated by the rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains. Current standard-of-care regimens are often lengthy and ineffective against resistant forms, necessitating urgent novel therapeutics. The mycobacterial cell wall, with its unique architecture of arabinogalactan, peptidoglycan, and mycolic acids, is a validated drug target due to its essential role in bacterial survival and virulence.

This comprehensive review synthesized recent advances in anti-tuberculosis drug discovery, focusing on the mycobacterial cell wall as a validated target. It explored both established and emerging targets within major biosynthetic pathways. The authors moved beyond conventional enzymatic inhibition, investigating a multidimensional framework that includes various novel mechanisms for disrupting cell wall integrity and bacterial survival.

The review identified several evolving strategies for targeting Mycobacterium tuberculosis beyond traditional enzymatic inhibition. These include direct disruption of cell wall integrity through alternative mechanisms, interference with bacterial energy metabolism and regulatory networks, and blocking the secretion and transport of essential cell wall components.

The review highlights the potential of harnessing host-directed therapies and antimicrobial peptides to augment the immune response and directly attack mycobacteria. Furthermore, it explored the utility of nanotechnology-based delivery systems to improve drug targeting and efficacy. By integrating discoveries across these diverse fronts, the review provides a forward-looking perspective on developing ultra-short, highly effective, and resistance-proof tuberculosis regimens.