Molecular Glue Degraders of TEM β‐Lactamases by Periplasmic Protease DegP

ABSTRACT Antimicrobial resistance is one of the most serious challenges to global health, yet the development of new molecules with novel mechanisms of action to combat resistance is lacking. In this study, we report the discovery of molecular glues that recruit TEM‐family β‐lactamases to the bacterial protease DegP for degradation. β‐Lactamase inhibitor tazobactam was found to accelerate degradation of TEM β‐lactamases by DegP, which was further enhanced by linkerless incorporation of dipeptide motifs enriched among DegP substrates. The resulting molecular glue degraders showed improved synergy with β‐lactam piperacillin against resistant Escherichia coli compared to tazobactam, as well as good pharmacokinetic properties for oral dosing. Collectively, this work establishes periplasmic targeted protein degradation as a promising new mechanism for combating β‐lactamase resistance.