Understanding the key challenges in tuberculosis drug discovery: what does the future hold?

Introduction Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health concern. It spreads through airborne droplets and has a high mortality rate, particularly without treatment. Drug resistance is rising, with treatments against multidrug-resistant TB (MDR-TB) showing poor treatment success rates. The thick, lipid-rich wall of Mtb and its slow growth reduce antibiotic effectiveness, requiring long treatment courses of 4-6 months. Current therapies often fail against drug-resistant strains, highlighting the urgent need for new, short-course treatment, affordable, and combination-friendly drugs. Areas covered Within this perspective, the authors review and comment on the following topics regarding Mtb resistance emergence and treatment strategies: i) Existing treatment ii) Resistance evolution in Mtb; iii) Key challenges in drug discovery targeting Mtb; iv) emerging strategies and recent advances in Mtb drug discovery, and v) Next-generation approaches. Literature was identified through a search of PubMed, google scholar, and web of science, from January 2010 to March 2025. Expert opinion AI is accelerating the discovery of bioavailable and safe preclinical drug candidates for TB, though data limitations and biological complexity remain challenging. Future progress requires multi-modal models, open-access datasets, and interdisciplinary collaboration.