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
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Pok Fu Lam, Hong Kong.
Department of Microbiology, The University of Hong Kong, Sassoon Road, Pok Fu Lam, Hong Kong.
Nat Commun. 2018 Jan 30;9(1):439. 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.
耐药超级细菌对人类健康构成巨大威胁。产金属β-内酰胺酶（MBL）的肠杆菌科细菌感染，例如新德里金属β-内酰胺酶1（NDM-1）感染，很难治疗。开发有效的MBL抑制剂以恢复现有抗生素的疗效非常必要。然而，到目前为止此类抑制剂尚未在临床上可用。在此我们表明，一种抗幽门螺杆菌药物，枸橼酸铋钾（CBS）以及相关的Bi(III)化合物通过该机制不可逆地抑制不同类型的MBL，如X射线晶体学所示，一个Bi(III)取代两个Zn(II)离子，导致Zn(II)辅因子释放。CBS在体外恢复了美罗培南（MER）对MBL阳性细菌的疗效，并且在小鼠感染模型中，重要的是，还减缓了NDM-1阳性细菌中更高水平耐药性的产生。本研究证明了Bi(III)化合物作为首个广谱B1 MBL抑制剂与现有碳青霉烯类药物联合治疗MBL阳性细菌感染的巨大潜力。
