L-Histidine resensitizes multidrug-resistant bacteria to carbapenems by inhibiting New Delhi metallo-β-lactamase activity
- 1Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- 2Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, China
- 3Institute of Comparative Medicine, Yangzhou University, Yangzhou, China
Abstract
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. Author summary: The rise of carbapenem-resistant bacteria, particularly those producing NDM enzymes, has left clinicians with few effective treatment options for severe Gram-negative bacterial infections. In this study, we show that L-histidine (L-His), a naturally occurring amino acid commonly used as a dietary supplement, can restore the killing of meropenem against NDM-producing superbugs. L-His works by competitively binding to the zinc ions in the NDM enzyme’s active site and disrupting intracellular Ni2+ homeostasis to suppress NDM activity via a non‑competitive mechanism. In both in vitro and in vivo infection, L-His supplementation significantly enhanced bacterial clearance by meropenem and improved survival, without causing detectable toxicity. While more studies are needed, our findings suggest a promising approach to rejuvenate existing antibiotics with a simple, safe, and natural metabolic adjuvant.
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BibTeX
@article{yin2026lhistidine,
title = {{L-Histidine resensitizes multidrug-resistant bacteria to carbapenems by inhibiting New Delhi metallo-β-lactamase activity}},
author = {Yanqing Yin and Sulan Hu and Dan Fang and Yanhu Huang and Miaomiao Huang and Suhong Liu and Zhiqiang Wang and Yuan Liu},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014728},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014728},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - L-Histidine resensitizes multidrug-resistant bacteria to carbapenems by inhibiting New Delhi metallo-β-lactamase activity
AU - Yanqing Yin
AU - Sulan Hu
AU - Dan Fang
AU - Yanhu Huang
AU - Miaomiao Huang
AU - Suhong Liu
AU - Zhiqiang Wang
AU - Yuan Liu
PY - 2026
DA - 2026/10/26
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014728
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014728
AB - 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. Author summary: The rise of carbapenem-resistant bacteria, particularly those producing NDM enzymes, has left clinicians with few effective treatment options for severe Gram-negative bacterial infections. In this study, we show that L-histidine (L-His), a naturally occurring amino acid commonly used as a dietary supplement, can restore the killing of meropenem against NDM-producing superbugs. L-His works by competitively binding to the zinc ions in the NDM enzyme’s active site and disrupting intracellular Ni2+ homeostasis to suppress NDM activity via a non‑competitive mechanism. In both in vitro and in vivo infection, L-His supplementation significantly enhanced bacterial clearance by meropenem and improved survival, without causing detectable toxicity. While more studies are needed, our findings suggest a promising approach to rejuvenate existing antibiotics with a simple, safe, and natural metabolic adjuvant.
SN - 1553-7374
SN - 1553-7366
ER -