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

Abstract

Antimicrobial resistance (AMR) proliferation and stagnant antibiotic innovation challenge infection control. Bacterial proteolysis-targeting chimeras (BacPROTACs) show promise in degrading resistance factors in Gram-positive pathogens but remain uncharacterized in clinically dominant Gram-negative species. We engineered NacssrA-1, a Gram-negative-specific BacPROTAC, to degrade β-lactamase CTX-M-14 via ClpXP. This bifunctional molecule demonstrated dual-binding specificity, dose-dependent proteolysis, and cefotaxime resensitization in resistant E. coli, enabling precision targeting of resistance mechanisms.