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
  • 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.

Products