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

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

  • Eur J Med Chem. 2022 Jan 15;228:113975. doi: 10.1016/j.ejmech.2021.113975.
Anna Proschak 1,  Giada Martinelli 2,  Denia Frank 2,  Marco J Rotter 1,  Steffen Brunst 1,  Lilia Weizel 1,  Luisa D Burgers 3,  Robert Fürst 3,  Ewgenij Proschak 1,  Izidor Sosič 4,  Stanislav Gobec 4,  Thomas A Wichelhaus 5
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue Str. 9, 60438, Frankfurt, Germany.
  • 2 Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Goethe-University, Paul-Ehrlich-Str. 40, 60596, Frankfurt, Germany.
  • 3 Institute of Pharmaceutical Biology, Goethe-University, Max-von-Laue Str. 9, 60438, Frankfurt, Germany.
  • 4 University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, SI, 1000, Ljubljana, Slovenia.
  • 5 Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Goethe-University, Paul-Ehrlich-Str. 40, 60596, Frankfurt, Germany. Electronic address: [email protected].
PMID: 34865870 DOI: 10.1016/j.ejmech.2021.113975
Abstract

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.

Keywords

Antibiotic resistance; Metal chelators; Metallo-β-lactamases; Nitroxoline.

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