Discovery of 3-methacylic acid substituted benzoxaboroles as dual metallo- and serine-β-lactamase inhibitors.

Carbapenem resistance is an ongoing clinical problem, largely driven by production of evolved serine β-lactamases (SBLs) and metallo-β-lactamases (MBLs). We here report a series of new 3-methacrylic acid-substituted benzoxaboroles as dual MBL/SBL inhibitors. Structure-activity relationship studies showed that the new compounds manifested nanomolar inhibition to the SBLs KPC-2 and OXA-48, and single-digit micromolar inhibition to the MBLs VIM-2, NDM-1, and NDM-5. Co-crystallographic analyses revealed their binding modes with VIM-2 and OXA-48, which are similar as those of taniborbactam and xeruborbactam. Bacterial assays demonstrated that compound 10 can potentiate meropenem against multidrug-resistant Gram-negative strains. This work provides new lead compounds and structural basis for developing new drug candidates against MBL/SBL-mediated carbapenem resistance.