1,2-Isoselenazol-3(2H)-one derivatives as NDM-1 inhibitors displaying synergistic antimicrobial effects with meropenem on NDM-1 producing clinical isolates

The New Delhi beta-Lactamase 1 (NDM-1), one of the most prevalent types of metallo-beta-lactamases, has attracted extensive attention since its discovery. Extensive efforts have been made to develop inhibitor of NDM-1, how-ever, no inhibitor is available clinically so far. It is reported that Benzo[d][1,2]selenazol-3(2H)-one derivatives as covalent NDM-1 inhibitors can restore the efficacy of meropenem against NDM-1producing strains. In this study, 38 novel benzo or pyrido[d][1,2]selenazol-3(2H)-one derivatives were designed based on NDM-1 protein structure and structure-activity relationships study. Representative compound 15l exhibits significant synergistic antibacterial activity with meropenem against NDM-1 producing carbapenem-resistant Enterobacteriaceae (CRE) isolates, especially clinical CRE isolates (FIC indices ranging from 0.0625 to 0.25). ESI-MS analysis demonstrats that 15l covalently binds to NDM-1 enzyme, and the IC50 is 11.25 mu M. In conclusion, this study has developed a novel scaffold with higher activity to enrich the structural types of benzo[d][1,2]selenazol-3(2H)-one de-rivatives. Compound 15l can be considered as a promising lead compound to restore the antibacterial effect of meropenem in combating life-threatening CRE.

Automated summary

This study designed and developed a novel scaffold of benzo[d][1,2]selenazol-3(2H)-one derivatives, and the representative compound 15l showed strong antibacterial activity when combined with meropenem, with the potential to restore the antibacterial effect against clinically resistant Enterobacteriaceae strains.