{
  "abstract": "Multidrug-resistant (MDR) Gram-negative bacteria pose a critical global health threat, while polymyxins remain a last-line therapy. However, their clinical use is limited by nephrotoxicity. Human oligopeptide transporter 2 (hPepT2) is a membrane transporter mediating the reabsorption of polymyxins in renal cells and contributes to their nephrotoxicity, but the molecular basis of their interaction remains unclear. Here, we investigated the structure-interaction relationship (SIR) of polymyxins with hPepT2 by integrating computational, chemical, and cell biology approaches. Bioinformatic modeling predicted an outward-facing hPepT2 structure and a potential transport pathway, with polymyxins interacting at the lateral opening, particularly E214, D215, D317, D342, and E622. Transporter mutagenesis and molecular analyses confirmed that D215 is critical for polymyxin binding, while other residues influence transporter turnover and/or expression. We subsequently synthesized polymyxin analogs with modifications at Dab1, Dab3, Dab5, and Dab9 of polymyxins, which reduced interactions with hPepT2. Notably, alanine substitution at Dab3 reduced nephrotoxicity in mice while retaining antibacterial activity. Overall, this proof-of-concept study demonstrates that the hPepT2-polymyxin SIR model provides a viable strategy for developing novel, safer lipopeptide antibiotics.",
  "abstract_shown": true,
  "affiliations": [
    "National Glycoengineering Research Center, Shandong University, Qingdao, China",
    "Molecular Drug Development Group, Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia",
    "Biomedicine Discovery Institute, Infection Program, Monash University, Melbourne, Australia",
    "Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand",
    "Department of Industrial and Molecular Pharmaceutics, College of Pharmacy, Purdue University, West Lafayette, United States",
    "Save Sight Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xukai Jiang",
      "orcid": "0000-0002-3624-8732"
    },
    {
      "affs": [
        1
      ],
      "name": "Yining Luo"
    },
    {
      "affs": [
        2
      ],
      "name": "Mohammad AK Azad"
    },
    {
      "affs": [
        0
      ],
      "name": "Limei Xu"
    },
    {
      "affs": [
        0
      ],
      "name": "Min Xiao"
    },
    {
      "affs": [
        2
      ],
      "name": "Tony Velkov"
    },
    {
      "affs": [
        2
      ],
      "name": "Kade D Roberts"
    },
    {
      "affs": [
        3
      ],
      "name": "Visanu Thamlikitkul"
    },
    {
      "affs": [
        4
      ],
      "name": "Qi Tony Zhou"
    },
    {
      "affs": [
        1,
        5
      ],
      "name": "Fanfan Zhou",
      "orcid": "0000-0002-1982-1541"
    },
    {
      "affs": [
        2
      ],
      "name": "Jian Li",
      "orcid": "0000-0001-7953-8230"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9rc7jvn08gjm6.bib",
  "cited_by": 0,
  "doi": "10.7554/elife.111387",
  "fulltext_url": "https://elifesciences.org/articles/111387",
  "id": "9rc7jvn08gjm6",
  "issns": [
    "2050-084X"
  ],
  "landing_url": "https://elifesciences.org/articles/111387",
  "language": "eng",
  "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": [
    [
      "elife",
      "biochemistry-chemical-biology"
    ],
    [
      "heading",
      "Biochemistry and Chemical Biology"
    ],
    [
      "heading",
      "Research Article"
    ],
    [
      "openalex",
      "2730|Drug Transport and Resistance Mechanisms"
    ]
  ],
  "openalex": "W7171738847",
  "pdf_url": "https://cdn.elifesciences.org/articles/111387/elife-111387-v1.pdf",
  "pmcid": "PMC13719170",
  "pmid": "42955842",
  "published": "2026-10-29",
  "publisher": "eLife Sciences Publications",
  "ris": "https://research.draconitic.com/paper/9rc7jvn08gjm6.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:25Z",
      "native_id": "111387",
      "source": "elife",
      "url": "https://elifesciences.org/articles/111387"
    },
    {
      "first_seen": "2026-10-31T00:20:39Z",
      "native_id": "MED:42955842",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42955842"
    },
    {
      "first_seen": "2026-11-02T12:23:03Z",
      "native_id": "PMC13719170",
      "source": "pmc",
      "url": "https://doi.org/10.7554/elife.111387"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Drug Transport and Resistance Mechanisms",
      "subfield": "oncology"
    }
  ],
  "title": "Lateral opening site of human oligopeptide transporter 2 plays a key role in the interaction with polymyxins",
  "title_text": "Lateral opening site of human oligopeptide transporter 2 plays a key role in the interaction with polymyxins",
  "type": "peer-reviewed",
  "updated_at": "2026-11-02T12:23:03Z",
  "url": "https://research.draconitic.com/paper/9rc7jvn08gjm6",
  "venue": "eLife",
  "versions": []
}