SsrA-based design of BacPROTACs for β-lactamase degradation in Gram-negative bacteria

Antimicrobial resistance (AMR) challenges infection control amid limited antibiotic innovation. While bacterial proteolysis-targeting chimeras (BacPROTACs) degrade resistance factors in Gram-positive pathogens, their application in critical Gram-negative species remains unexplored. We engineered a Gram-negative-specific BacPROTAC, NacssrA-1, to degrade the β-lactamase CTX-M-14 via ClpXP. This molecule demonstrated dual-binding specificity, dose-dependent proteolysis, and cefotaxime resensitization in resistant E. coli, enabling precision AMR targeting.