n-n--ethylenediamine-disuccinic-acid and nitroxoline

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.

Topics: Anti-Bacterial Agents; beta-Lactamase Inhibitors; beta-Lactamases; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Gram-Negative Bacteria; Humans; Microbial Sensitivity Tests; Molecular Structure; Nitroquinolines; Recombinant Proteins; Structure-Activity Relationship