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

Plasmid-mediated New Delhi metallo-β-lactamase (NDM)-producing Gram-negative pathogens have severely undermined the clinical utility of carbapenems, the last-resort antibiotics for multidrug-resistant infections. Given the limited pipeline of novel antibiotics, there is an urgent need for more effective anti-infective strategies. Through untargeted metabolomics and function screening, we find that L-histidine (L-His), a key downregulated metabolite in NDM-positive bacteria, remarkably restores carbapenem susceptibility. Mechanistically, L‑His acts through two complementary pathways: (i) direct competitive inhibition of NDM enzymatic activity via zinc chelation at the active site, and (ii) upregulation of the nickel ion transport gene cluster nikABCDE, which increases intracellular Ni2+ accumulation and further suppresses NDM function through non‑competitive inhibition. Overexpression of nikA potentiates the bactericidal activity of meropenem, whereas deletion of nikAB attenuates the synergistic effect of L‑His and meropenem. 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. Collectively, our findings reveal L‑His as a multi‑mechanistic metabolic adjuvant that combines direct enzyme inhibition with disruption of metal homeostasis, positioning it as a promising therapeutic strategy against NDM‑positive carbapenem‑resistant infections.