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Bismuth antimicrobial drugs serve as broad-spectrum metallo-β-lactamase inhibitors

Author

Listed:
  • Runming Wang

    (The University of Hong Kong
    The University of Hong Kong)

  • Tsz-Pui Lai

    (The University of Hong Kong)

  • Peng Gao

    (The University of Hong Kong
    The University of Hong Kong)

  • Hongmin Zhang

    (The University of Hong Kong
    Southern University of Science and Technology)

  • Pak-Leung Ho

    (The University of Hong Kong
    The University of Hong Kong
    The University of Hong Kong)

  • Patrick Chiu-Yat Woo

    (The University of Hong Kong
    The University of Hong Kong
    The University of Hong Kong)

  • Guixing Ma

    (Southern University of Science and Technology)

  • Richard Yi-Tsun Kao

    (The University of Hong Kong
    The University of Hong Kong
    The University of Hong Kong)

  • Hongyan Li

    (The University of Hong Kong)

  • Hongzhe Sun

    (The University of Hong Kong)

Abstract

Drug-resistant superbugs pose a huge threat to human health. Infections by Enterobacteriaceae producing metallo-β-lactamases (MBLs), e.g., New Delhi metallo-β-lactamase 1 (NDM-1) are very difficult to treat. Development of effective MBL inhibitors to revive the efficacy of existing antibiotics is highly desirable. However, such inhibitors are not clinically available till now. Here we show that an anti-Helicobacter pylori drug, colloidal bismuth subcitrate (CBS), and related Bi(III) compounds irreversibly inhibit different types of MBLs via the mechanism, with one Bi(III) displacing two Zn(II) ions as revealed by X-ray crystallography, leading to the release of Zn(II) cofactors. CBS restores meropenem (MER) efficacy against MBL-positive bacteria in vitro, and in mice infection model, importantly, also slows down the development of higher-level resistance in NDM-1-positive bacteria. This study demonstrates a high potential of Bi(III) compounds as the first broad-spectrum B1 MBL inhibitors to treat MBL-positive bacterial infection in conjunction with existing carbapenems.

Suggested Citation

  • Runming Wang & Tsz-Pui Lai & Peng Gao & Hongmin Zhang & Pak-Leung Ho & Patrick Chiu-Yat Woo & Guixing Ma & Richard Yi-Tsun Kao & Hongyan Li & Hongzhe Sun, 2018. "Bismuth antimicrobial drugs serve as broad-spectrum metallo-β-lactamase inhibitors," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-02828-6
    DOI: 10.1038/s41467-018-02828-6
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    Cited by:

    1. Erik Svensson Grape & Victoria Rooth & Mathias Nero & Tom Willhammar & A. Ken Inge, 2022. "Structure of the active pharmaceutical ingredient bismuth subsalicylate," Nature Communications, Nature, vol. 13(1), pages 1-7, December.
    2. Chenyuan Wang & Yushan Xia & Runming Wang & Jingru Li & Chun-Lung Chan & Richard Yi-Tsun Kao & Patrick H. Toy & Pak-Leung Ho & Hongyan Li & Hongzhe Sun, 2023. "Metallo-sideromycin as a dual functional complex for combating antimicrobial resistance," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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