{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, China",
    "Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, China",
    "Institute of Comparative Medicine, Yangzhou University, Yangzhou, China"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yanqing Yin"
    },
    {
      "affs": [
        0
      ],
      "name": "Sulan Hu"
    },
    {
      "affs": [
        0
      ],
      "name": "Dan Fang"
    },
    {
      "affs": [
        0
      ],
      "name": "Yanhu Huang"
    },
    {
      "affs": [
        0
      ],
      "name": "Miaomiao Huang"
    },
    {
      "affs": [
        0
      ],
      "name": "Suhong Liu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Zhiqiang Wang"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Yuan Liu",
      "orcid": "0000-0002-9622-6471"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8n8ja96s0qhqw.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.ppat.1014728",
  "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014728",
  "id": "8n8ja96s0qhqw",
  "issns": [
    "1553-7374",
    "1553-7366"
  ],
  "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014728",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Animal Studies"
    ],
    [
      "heading",
      "Antibiotic Resistance"
    ],
    [
      "heading",
      "Antibiotics"
    ],
    [
      "heading",
      "Antimicrobial Resistance"
    ],
    [
      "heading",
      "Antimicrobials"
    ],
    [
      "heading",
      "Bacteria"
    ],
    [
      "heading",
      "Bacterial Pathogens"
    ],
    [
      "heading",
      "Biochemistry"
    ],
    [
      "heading",
      "Biology and Life Sciences"
    ],
    [
      "heading",
      "Chemical Elements"
    ],
    [
      "heading",
      "Chemistry"
    ],
    [
      "heading",
      "Drugs"
    ],
    [
      "heading",
      "Enterobacteriaceae"
    ],
    [
      "heading",
      "Enzyme Inhibitors"
    ],
    [
      "heading",
      "Enzymology"
    ],
    [
      "heading",
      "Escherichia"
    ],
    [
      "heading",
      "Escherichia Coli"
    ],
    [
      "heading",
      "Experimental Organism Systems"
    ],
    [
      "heading",
      "Gut Bacteria"
    ],
    [
      "heading",
      "Medical Microbiology"
    ],
    [
      "heading",
      "Medicine and Health Sciences"
    ],
    [
      "heading",
      "Metabolism"
    ],
    [
      "heading",
      "Metabolites"
    ],
    [
      "heading",
      "Metabolomics"
    ],
    [
      "heading",
      "Microbial Control"
    ],
    [
      "heading",
      "Microbial Pathogens"
    ],
    [
      "heading",
      "Microbiology"
    ],
    [
      "heading",
      "Model Organisms"
    ],
    [
      "heading",
      "Nickel"
    ],
    [
      "heading",
      "Organisms"
    ],
    [
      "heading",
      "Pathogens"
    ],
    [
      "heading",
      "Pathology and Laboratory Medicine"
    ],
    [
      "heading",
      "Pharmacology"
    ],
    [
      "heading",
      "Physical Sciences"
    ],
    [
      "heading",
      "Prokaryotic Models"
    ],
    [
      "heading",
      "Research Article"
    ],
    [
      "heading",
      "Research and Analysis Methods"
    ],
    [
      "heading",
      "Zinc"
    ],
    [
      "openalex",
      "1313|Antibiotic Resistance in Bacteria"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Enzymology/Enzyme inhibitors"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Metabolism/Metabolites"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Metabolism/Metabolomics"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Bacterial pathogens/Escherichia coli"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Microbial control/Antimicrobial resistance/Antibiotic resistance"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Microbial control/Antimicrobials/Antibiotics"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Bacteria/Enterobacteriaceae/Escherichia/Escherichia coli"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Bacteria/Gut bacteria/Escherichia/Escherichia coli"
    ],
    [
      "plos",
      "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Bacterial pathogens/Escherichia coli"
    ],
    [
      "plos",
      "/Medicine and health sciences/Pharmacology/Antimicrobial resistance/Antibiotic resistance"
    ],
    [
      "plos",
      "/Medicine and health sciences/Pharmacology/Drugs/Antimicrobials/Antibiotics"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Chemical elements/Nickel"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Chemical elements/Zinc"
    ],
    [
      "plos",
      "/Research and analysis methods/Animal studies/Experimental organism systems/Model organisms/Escherichia coli"
    ],
    [
      "plos",
      "/Research and analysis methods/Animal studies/Experimental organism systems/Prokaryotic models/Escherichia coli"
    ],
    [
      "plos",
      "/Research and analysis methods/Model organisms/Escherichia coli"
    ]
  ],
  "openalex": "W7223667843",
  "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014728&type=printable",
  "pmcid": "PMC13727045",
  "pmid": "42932391",
  "published": "2026-10-26",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/8n8ja96s0qhqw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:17Z",
      "native_id": "10.1371/journal.ppat.1014728",
      "source": "plos",
      "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014728"
    },
    {
      "first_seen": "2026-11-05T12:23:15Z",
      "native_id": "PMC13727045",
      "source": "pmc",
      "url": "https://doi.org/10.1371/journal.ppat.1014728"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "plos:enzymology",
      "subfield": "enzymology-metabolism"
    },
    {
      "field": "biochemistry",
      "origin": "heading:Metabolomics",
      "subfield": "proteomics-metabolomics"
    },
    {
      "field": "biology",
      "origin": "plos:microbiology",
      "subfield": "microbiology"
    },
    {
      "field": "chemistry",
      "origin": "heading:Chemistry",
      "subfield": "general"
    },
    {
      "field": "medicine",
      "origin": "plos:pharmacology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "L-Histidine resensitizes multidrug-resistant bacteria to carbapenems by inhibiting New Delhi metallo-β-lactamase activity",
  "title_text": "L-Histidine resensitizes multidrug-resistant bacteria to carbapenems by inhibiting New Delhi metallo-β-lactamase activity",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:22:51Z",
  "url": "https://research.draconitic.com/paper/8n8ja96s0qhqw",
  "venue": "PLOS Pathogens",
  "versions": []
}