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
  • 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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