2. Academic Validation
  3. Kinetics, Thermodynamics, and Structural Effects of Quinoline-2-Carboxylates, Zinc-Binding Inhibitors of New Delhi Metallo-β-lactamase-1 Re-sensitizing Multidrug-Resistant Bacteria for Carbapenems

Kinetics, Thermodynamics, and Structural Effects of Quinoline-2-Carboxylates, Zinc-Binding Inhibitors of New Delhi Metallo-β-lactamase-1 Re-sensitizing Multidrug-Resistant Bacteria for Carbapenems

  • J Med Chem. 2023 Sep 14;66(17):11761-11791. doi: 10.1021/acs.jmedchem.3c00171.
Yuwen Jia 1,  Barbara Schroeder 1,  Yvonne Pfeifer 2,  Christopher Fröhlich 3,  Lihua Deng 1,  Christoph Arkona 1,  Benno Kuropka 4,  Jana Sticht 4,  Kenichi Ataka 5,  Silke Bergemann 1,  Gerhard Wolber 1,  Christoph Nitsche 6,  Martin Mielke 7,  Hanna-Kirsti S Leiros 3,  Guido Werner 2,  Jörg Rademann 1
Affiliations

Affiliations

  • 1 Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, Berlin 14195, Germany.
  • 2 FG13 Nosocomial Pathogens and Antibiotic Resistances, Department of Infectious Diseases, Robert Koch Institute, Burgstraße 37, Wernigerode 38855, Germany.
  • 3 Department of Chemistry, Faculty of Science and Technology, UiT The Arctic University of Norway, Tromsø 9037, Norway.
  • 4 Core Facility BioSupraMol, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, Berlin 14195, Germany.
  • 5 Department of Physics, Freie Universität Berlin, Arnimallee 14, Berlin 14195, Germany.
  • 6 Research School of Chemistry, Australian National University, Canberra 2601, Australian Capital Territory, Australia.
  • 7 Department of Infectious Diseases, Robert Koch Institute, Nordufer 20, Berlin 13353, Germany.
PMID: 37585683 DOI: 10.1021/acs.jmedchem.3c00171
Abstract

Carbapenem resistance mediated by metallo-β-lactamases (MBL) such as New Delhi metallo-β-lactamase-1 (NDM-1) has become a major factor threatening the efficacy of essential β-lactam Antibiotics. Starting from hit fragment dipicolinic acid (DPA), 8-hydroxy- and 8-sulfonamido-quinoline-2-carboxylic acids were developed as inhibitors of NDM-1 with highly improved inhibitory activity and binding affinity. The most active compounds formed reversibly inactive ternary protein-inhibitor complexes with two zinc ions as proven by native protein mass spectrometry and bio-layer interferometry. Modification of the NDM-1 structure with remarkable entropic gain was shown by isothermal titration calorimetry and NMR spectroscopy of isotopically labeled protein. The best compounds were potent inhibitors of NDM-1 and other representative MBL with no or little inhibition of human zinc-binding enzymes. These inhibitors significantly reduced the minimum inhibitory concentrations (MIC) of meropenem for multidrug-resistant bacteria recombinantly expressing blaNDM-1 as well as for several multidrug-resistant clinical strains at concentrations non-toxic to human cells.

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