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

Runming Wang, Tsz-Pui Lai, Peng Gao, Hongmin Zhang, Pak-Leung Ho, Patrick Chiu-Yat Woo, Guixing Ma, Richard Yi-Tsun Kao, Hongyan Li and Hongzhe Sun ()
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Runming Wang: The University of Hong Kong
Tsz-Pui Lai: The University of Hong Kong
Peng Gao: The University of Hong Kong
Hongmin Zhang: The University of Hong Kong
Pak-Leung Ho: The University of Hong Kong
Patrick Chiu-Yat Woo: The University of Hong Kong
Guixing Ma: Southern University of Science and Technology
Richard Yi-Tsun Kao: The University of Hong Kong
Hongyan Li: The University of Hong Kong
Hongzhe Sun: The University of Hong Kong

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-02828-6

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