L-Histidine resensitizes multidrug-resistant bacteria to carbapenems by inhibiting New Delhi metallo-β-lactamase activity.

L-histidine (L-His) remarkably restores carbapenem susceptibility in plasmid-mediated NDM-producing Gram-negative pathogens, enabling meropenem synergy through metal-targeting mechanisms.

• Why it matters: Plasmid-mediated NDM enzymes undermine carbapenems, the last-resort antibiotics, and the limited pipeline of new drugs creates an urgent need for effective anti-infective adjuvants.
• What they did: Using untargeted metabolomics and function screening, the study shows L-His inhibits NDM via zinc chelation and upregulates nikABCDE to increase intracellular Ni2+; nikA overexpression enhances meropenem killing, while nikAB deletion attenuates L-His–meropenem synergy.
• The result: In a murine peritonitis–sepsis model, co-administration of L-His with meropenem significantly improves survival and reduces bacterial burden with a favorable safety profile.