5XP9

Crystal structure of Bismuth bound NDM-1

Summary for 5XP9

• Entry DOI: 10.2210/pdb5xp9/pdb
• Descriptor: Metallo-beta-lactamase type 2, Bismuth(III) ION, GLYCEROL, ... (4 entities in total)
• Functional Keywords: antibiotics resistance, beta-lactamase, metallodrug, bismuth, hydrolase
• Biological source: Klebsiella pneumoniae
• Cellular location: Periplasm : C7C422
• Total number of polymer chains: 1
• Total formula weight: 26019.97

Authors

Zhang, H.,Ma, G.,Lai, T.P.,Sun, H. (deposition date: 2017-06-01, release date: 2018-03-07, Last modification date: 2023-11-22)

Primary citation

Wang, R.,Lai, T.P.,Gao, P.,Zhang, H.,Ho, P.L.,Woo, P.C.,Ma, G.,Kao, R.Y.,Li, H.,Sun, H.
Bismuth antimicrobial drugs serve as broad-spectrum metallo-beta-lactamase inhibitors
Nat Commun, 9:439-439, 2018

PubMed 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.

PubMed: 29382822
DOI: 10.1038/s41467-018-02828-6

Experimental method

X-RAY DIFFRACTION (1.55 Å)