Breaking New Ground in the Fight Against Tuberculosis

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Tuberculosis (TB) continues to threaten global health, with the growing prevalence of drug-resistant strains making the development of new treatments more urgent than ever. In an exciting breakthrough, researchers are targeting the essential protein degradation system of Mycobacterium tuberculosis (Mtb) to develop innovative drugs. This system, composed of the ClpC1 ATPase and the P1P2 protease, is vital for Mtb’s survival. Scientists have synthesized and enhanced natural cyclic peptides—cyclomarin A, ecumicin, and rufomycin—that selectively bind to ClpC1, showing remarkable bactericidal activity. These peptides are now being repurposed to create a novel class of antibacterials called Bacterial Proteolysis-Targeted Chimeras (BacPROTACs), designed to degrade essential mycobacterial proteins and disrupt their survival mechanisms.

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This groundbreaking research aims to leverage advanced proteomic technologies to refine BacPROTACs and assess their efficacy. The focus includes developing dimeric BacPROTACs to target the ClpC1 degradation system itself and heterobivalent BacPROTACs that simultaneously degrade multiple essential proteins. Rigorous testing in pre-clinical TB models and against the challenging NTM species M. abscessus is already underway. By significantly shortening treatment durations and addressing antimicrobial resistance, this approach could transform TB therapy and provide a powerful new weapon in the fight against one of the world’s deadliest infectious diseases.