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

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.