Discovery Of 3-Aryl Substituted Benzoxaboroles As Broad-Spectrum Inhibitors Of Serine- And Metallo-8-Lactamases

The production of 8-lactamases represents the main cause of resistance to clinically important 8-lactam antibiotics. Boron containing compounds have been demonstrated as promising broad-spectrum 8-lactamase inhibitors to combat 8-lactam resistance. Here we report a series of 3-aryl substituted benzoxaborole derivatives, which manifested broad-spectrum inhibition to representative serine-8-lactamases (SBLs) and metallo-8-lactamases (MBLs). The most potent inhibitor 9f displayed an IC50 value of 86 nM to KPC-2 SBL and micromolar inhibitory activity towards other tested enzymes. Cell-based assays further revealed that 9f was able to significantly reduce the MICs of meropenem in clinically isolated KPC-2-producing bacterial strains and it showed no apparent toxicity in HEK293T cells.