SsrA-Based Targeted Protein Degradation in Escherichia coli.

Targeted protein degradation is an emerging concept of drug discovery to selectively eliminate the pathogenic proteins by activating their degradation in cells. The proteolysis-targeting chimeras (PROTACs) are bifunctional small molecules that induce the degradation of a protein of interest (POI) by proteasome. Here we describe a method that utilizes an ssrA-based BacPROTAC (bacterial PROTACs) to target the drug-resistant proteins CTX-M-14, a class A β-lactamase commonly found in extended-spectrum beta-lactamase (ESBL) plasmids of antimicrobial resistance (AMR) bacteria. This strategy could resensitize the drug-resistant bacteria and revive previously disregarded antibiotics, opens up a new avenue for therapeutic development of AMR bacteria.