Degrading Resistance on Command: LAMP‐D Reframes Targeted Protein Degradation as a Photochemical Problem

Antimicrobial resistance (AMR) demands therapeutic strategies that do not inhibit bacterial enzymes but target protein elimination. In this highlight, Stevens‐Cullinane, Hess, and coworkers report light‐activated metal‐dependent protein degradation (LAMP‐D), which uses a ruthenium photosensitizer tethered to a targeting ligand to degrade New Delhi metallo‐β‐lactamase 1 (NDM‐1) in the presence of blue light. Unlike proteolysis‐targeting chimeras (PROTACs) or BacPROTACs, LAMP‐D requires no endogenous ligases, no proteasomal machinery, and no ternary complex formation. It delivers a light‐activated photochemical degrader directly to the protein surface. The result is light‐triggered NDM‐1 degradation accompanied by a >100‐fold enhancement in enzyme inhibition in vitro and a 53‐fold rescue of meropenem activity in live Escherichia coli ( E. coli ), achieved without mammalian cytotoxicity. In addition to its direct application to NDM‐1, it represents a conceptual shift in targeted protein degradation from cellular machinery to light‐driven catalysis, opening new avenues for addressing resistance in Gram‐negative pathogens.