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

ABSTRACT: In the search for new inhibitors of bacterial metallo-?-lactamases (MBLs), a series of commonly used small molecule carboxylic acid derivatives were evaluated for their ability to inhibit New Delhi metallo-?-lactamase (NDM)-, Verona integron-encoded metallo-?-lactamase (VIM)-, and imipenemase (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 ?M range. Binding assays using isothermal titration calorimetry reveal that 3 and 5 bind zinc with high affinity with dissociation constant (K_d) values of 121 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 minimum inhibitory concentration (MIC) of Meropenem up to 128-fold against strains producing NDM- and VIM-type enzymes.

SUBMITTER: Tehrani KHME 

PROVIDER: S-EPMC7296533 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature