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.
Highlights
Drug-resistant superbugs pose a huge threat to human health
The antimicrobial activities of metal compounds with a β-lactam antibiotic were initially screened against a clinical isolate of New Delhi metallo-β-lactamase 1 (NDM-1)-positive E. coli, hereafter denoted as New Delhi metallo-β-lactamases (NDMs)-HK (Supplementary Table 1)[33]
The NDM-1-producing strain was confirmed to be resistant to a carbapenem, meropenem (MER) as judged by its minimal inhibitory concentration (MIC) of 16 μg mL−1, which is higher than the breakpoint value (>8 μg mL−1) for MER against Enterobacteriaceae defined by European Committee on Antimicrobial Susceptibility Testing (EUCAST)[34]
Summary
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. Combination therapy comprising an available antibiotic and a nonantibiotic that is usually an inhibitor of β-lactamase has been considered as a more economical and effective alternative than development of monotherapy with new antibiotics[2,13,14,15,16,17] Such combination therapies are currently used clinically to treat infection from serine-β-lactamases (SBLs)-positive bacteria e.g., Augmentin® (amoxicillin/clavulanate), Zosyn® (piperacillin/tazobactam), and recent Avycaz® (ceftazidime/ avibactam). Our studies strongly suggest that Bi(III) drugs or compounds might be repositioned or developed as the first broad-spectrum inhibitors of MBLs, in particular, class B1 MBLs. This study provides a new opportunity to design effective broadspectrum MBL inhibitors for the treatment of infection caused by MBL-positive bacteria together with β-lactam antibiotics
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