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 NDM, VIM, and IMP-type enzymes. Nitrilotriacetic acid 3 and N-(phosphonomethyl)iminodiacetic acid 5 showed promising activity especially against NDM-1 and VIM-2 with IC50 values in the low-to-sub µM range. Binding assays using isothermal titration calorimetry reveal that 3 and 5 bind zinc with high affinity with Kd values of 121 nM and 56 nM respectively. The in vitro biological activity of 3 and 5 against E. coli expressing NDM-1 was evaluated in checkerboard format demonstrating a strong synergistic relationship for both compounds when combined with meropenem. Compounds 3 and 5 were then tested against 35 pathogenic strains expressing MBLs of the NDM, VIM, or IMP classes. Notably, when combined with meropenem, compounds 3 and 5 were found to lower the MIC of meropenem up to 128-fold against strains producing NDM and VIM type enzymes.