Nitroxoline and its derivatives are potent inhibitors of metallo-β-lactamases.

Autor: Proschak A; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue Str. 9, 60438, Frankfurt, Germany., Martinelli G; Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Goethe-University, Paul-Ehrlich-Str. 40, 60596, Frankfurt, Germany., Frank D; Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Goethe-University, Paul-Ehrlich-Str. 40, 60596, Frankfurt, Germany., Rotter MJ; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue Str. 9, 60438, Frankfurt, Germany., Brunst S; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue Str. 9, 60438, Frankfurt, Germany., Weizel L; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue Str. 9, 60438, Frankfurt, Germany., Burgers LD; Institute of Pharmaceutical Biology, Goethe-University, Max-von-Laue Str. 9, 60438, Frankfurt, Germany., Fürst R; Institute of Pharmaceutical Biology, Goethe-University, Max-von-Laue Str. 9, 60438, Frankfurt, Germany., Proschak E; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue Str. 9, 60438, Frankfurt, Germany., Sosič I; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, SI, 1000, Ljubljana, Slovenia., Gobec S; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, SI, 1000, Ljubljana, Slovenia., Wichelhaus TA; Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Goethe-University, Paul-Ehrlich-Str. 40, 60596, Frankfurt, Germany. Electronic address: Wichelhaus@em.uni-frankfurt.de.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2022 Jan 15; Vol. 228, pp. 113975. Date of Electronic Publication: 2021 Nov 13.
DOI: 10.1016/j.ejmech.2021.113975
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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