The researchers found that L-histidine works through two complementary mechanisms. First, it directly inhibits the NDM enzyme by chelating zinc at the active site, competing with the enzyme’s catalytic machinery. NDM requires zinc ions to break down carbapenems, so this competitive interference disables the bacteria’s primary defense against the drugs.

Second, L-histidine upregulates the nikABCDE nickel transport gene cluster, increasing intracellular accumulation of nickel ions. This excess nickel suppresses NDM function through a separate, non-competitive route, meaning the two effects attack the enzyme in distinct ways that reinforce each other.

Genetic experiments supported this pathway. When the researchers overexpressed nikA, the bactericidal activity of meropenem against NDM-positive bacteria increased. Conversely, deleting the nikAB genes weakened the synergy between L-histidine and meropenem, confirming that nickel transport is central to the resensitization effect.

The team then tested the combination in a murine peritonitis-sepsis model. Co-administration of L-histidine with meropenem significantly improved survival and reduced bacterial burden in the infected animals, and the treatment showed a favorable safety profile in the mice.

Because the pipeline of novel antibiotics remains limited, the authors argue that metabolic adjuvants like L-histidine offer a promising strategy against NDM-positive, carbapenem-resistant infections. By combining direct enzyme inhibition with disruption of bacterial metal homeostasis, a single endogenous metabolite can strip resistant pathogens of their defense and return existing antibiotics to clinical usefulness. The findings, reported from laboratory and animal studies, position L-histidine as a candidate therapeutic adjunct that would require further evaluation before human application.

Subject of Research: L-histidine as a metabolic adjuvant restoring carbapenem susceptibility in NDM-producing antibiotic-resistant bacteria

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

Article References: Yin, Y., Hu, S., Fang, D., Huang, Y., Huang, M., Liu, S., Wang, Z., & Liu, Y. (2026). L-Histidine resensitizes multidrug-resistant bacteria to carbapenems by inhibiting New Delhi metallo-β-lactamase activity. PLOS Pathogens, 22(10), e1014728. https://doi.org/10.1371/journal.ppat.1014728

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014728

Keywords: L-histidine, NDM, carbapenems, antibiotic resistance, metallo-beta-lactamase, meropenem, nickel transport, nikABCDE, metabolomics, sepsis, Gram-negative bacteria, antibiotic adjuvant