PROTACs as novel therapeutics against Mycobacterium tuberculosis: Current progress and future directions

Targeted Protein Degradation (TPD) has emerged as a transformative strategy in drug discovery, offering novel approaches to eliminate pathogenic proteins with high specificity. Unlike traditional small-molecule inhibitors, which often require sustained target engagement and are prone to resistance via target mutations, TPD harnesses the cell's endogenous ubiquitin-proteasome system to catalytically degrade pathogenic proteins, enabling potent and durable therapeutic effects. This review highlights the recent advances and potential of one such TPD technology, PROTACs against Mycobacterium tuberculosis. We discuss resistance mechanisms in bacteria along with various opportunities for PROTAC based degradation, explore challenges in achieving selectivity, and outline future directions for integrating PROTACs into anti-bacterial therapeutics. This emerging paradigm holds promise to revolutionize infectious disease treatment by offering targeted, mechanism-based eradication of disease-driving proteins. Looking forward, advances in medicinal chemistry, structural biology, and delivery platforms are expected to expand the scope and efficacy of various TPD strategies including PROTACs in infectious disease treatment.