BacPROTACs outperform inhibitors in Mycobacterium tuberculosis

Abstract Antibiotic discovery has long relied on occupancy-driven inhibition, leaving a vast number of potential bacterial targets undrugged. 1 Targeted protein degradation offers a mechanistically distinct alternative to inhibition, yet its application to antibacterial drug discovery remains largely unexplored. 2–4 Here we describe the development of first-in-class heterobifunctional bacterial proteolysis targeting chimeras (BacPROTACs) directed against an essential Mycobacterium tuberculosis protein, 4’-phosphopantetheinyl transferase (PptT). 5 Leveraging the modular architecture of BacPROTACs, we repurposed PptT inhibitors by incorporating them into degraders, yielding compounds with markedly improved antimycobacterial activity. Integrating in vitro and cellular approaches, we developed a characterisation pipeline to assess protein degradation in bacteria, applicable to future BacPROTAC programmes. Our study establishes targeted protein degradation as a strategy for antibacterial drug discovery.