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

• Published in: Journal of medicinal chemistry 2023-09, Vol.66 (17), p.11761-11791
• Main Authors: Jia, Yuwen, Schroeder, Barbara, Pfeifer, Yvonne, Fröhlich, Christopher, Deng, Lihua, Arkona, Christoph, Kuropka, Benno, Sticht, Jana, Ataka, Kenichi, Bergemann, Silke, Wolber, Gerhard, Nitsche, Christoph, Mielke, Martin, Leiros, Hanna-Kirsti S., Werner, Guido, Rademann, Jörg
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00171

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 bla NDM‑1 as well as for several multidrug-resistant clinical strains at concentrations non-toxic to human cells.