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.