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

• Published in: Nature communications Vol. 9; no. 1; pp. 439 - 12
• Main Authors: Wang, Runming, Lai, Tsz-Pui, Gao, Peng, Zhang, Hongmin, Ho, Pak-Leung, Woo, Patrick Chiu-Yat, Ma, Guixing, Kao, Richard Yi-Tsun, Li, Hongyan, Sun, Hongzhe
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.01.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 140/131; 140/58; 38/77; 631/154/1435; 631/326/22; 631/45/173; 64/60; 82/80; 82/83; Animals; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacology; Antibiotics; Antimicrobial agents; Bacteria; Bacterial diseases; beta-Lactam Resistance - drug effects; beta-Lactamase Inhibitors - pharmacology; beta-Lactamases - chemistry; beta-Lactamases - metabolism; Bismuth; Bismuth - chemistry; Bismuth - metabolism; Bismuth - pharmacology; Bismuth compounds; Carbapenems; Carbapenems - pharmacology; Catalytic Domain; Cofactors; Crystallography; Crystallography, X-Ray; Dogs; Drug Evaluation, Preclinical - methods; Drug resistance; Evolution, Molecular; Female; Helicobacter pylori; Humanities and Social Sciences; Inhibitors; Madin Darby Canine Kidney Cells - drug effects; Meropenem; Metallo-β-lactamase; Metallography; Mice, Inbred BALB C; Microbial Sensitivity Tests; multidisciplinary; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Peritonitis - drug therapy; Peritonitis - microbiology; Science; Science (multidisciplinary); X-ray crystallography; Zinc - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-02828-6

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. Metallo-β-lactamases (MBL) are zinc containing enzymes that cause resistance to β-lactam antibiotics. Here the authors show that the anti- Helicobacter pylori drug colloidal bismuth subcitrate inhibits MBLs by displacing the zinc ions with Bi(III), which is of great interest for the development of antibiotics.