Small Molecule Carboxylates Inhibit Metallo-β-lactamases and Resensitize Carbapenem-Resistant Bacteria to Meropenem.

In the search for new inhibitors of bacterial metallo-β-lactamases (MBLs), a series of commonly used small molecule carboxylic acid derivatives were evaluated for their ability to inhibit New Delhi metallo-β-lactamase (NDM)-, Verona integron-encoded metallo-β-lactamase (VIM)-, and imipenemase (IMP)-type enzymes. Nitrilotriacetic acid () and -(phosphonomethyl)iminodiacetic acid () showed promising activity especially against NDM-1 and VIM-2 with IC values in the low-to-sub μM range. Binding assays using isothermal titration calorimetry reveal that and bind zinc with high affinity with dissociation constant () values of 121 and 56 nM, respectively. The biological activity of and against expressing NDM-1 was evaluated in checkerboard format, demonstrating a strong synergistic relationship for both compounds when combined with Meropenem. Compounds and were then tested against 35 pathogenic strains expressing MBLs of the NDM, VIM, or IMP classes. Notably, when combined with Meropenem, compounds and were found to lower the minimum inhibitory concentration (MIC) of Meropenem up to 128-fold against strains producing NDM- and VIM-type enzymes.