Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue Str. 9, 60438, Frankfurt, Germany.
Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Goethe-University, Paul-Ehrlich-Str. 40, 60596, Frankfurt, Germany.
Eur J Med Chem. 2022 Jan 15;228:113975. doi: 10.1016/j.ejmech.2021.113975. Epub 2021 Nov 13.
Carbapenemases such as metallo-β-lactamases (MBLs) are spreading among Gram-negative bacterial pathogens. Infections due to these multidrug-resistant bacteria constitute a major global health challenge. Therapeutic strategies against carbapenemase producing bacteria include β-lactamase inhibitor combinations. Nitroxoline is a broad-spectrum antibiotic with restricted indication for urinary tract infections. In this study, we report on nitroxoline as an inhibitor of MBLs. We investigate the structure-activity relationships of nitroxoline derivatives considering in vitro MBL inhibitory potency in a fluorescence based assay using purified recombinant MBLs, NDM-1 and VIM-1. We investigated the most potent nitroxoline derivative in combination with imipenem against clinical isolates as well as transformants producing MBL by broth microdilution and time-kill kinetics. Our findings demonstrate that nitroxoline derivatives are potent MBL inhibitors and in combination with imipenem overcome MBL-mediated carbapenem resistance.
碳青霉烯酶（如金属β-内酰胺酶（MBLs））在革兰氏阴性细菌病原体中传播。这些多药耐药细菌引起的感染是一个主要的全球健康挑战。针对产碳青霉烯酶细菌的治疗策略包括β-内酰胺酶抑制剂联合用药。硝呋太尔是一种广谱抗生素，仅用于尿路感染。在这项研究中，我们报告了硝呋太尔作为 MBL 抑制剂。我们通过使用纯化的重组 MBL、NDM-1 和 VIM-1 进行荧光测定法，在体外研究了硝呋太尔衍生物的结构-活性关系，以评估其对 MBL 的抑制作用。我们研究了最有效的硝呋太尔衍生物与亚胺培南联合使用，通过肉汤微量稀释法和时间杀伤动力学，针对临床分离株以及产生 MBL 的转化株进行了研究。我们的研究结果表明，硝呋太尔衍生物是有效的 MBL 抑制剂，与亚胺培南联合使用可克服 MBL 介导的碳青霉烯类耐药性。
