Discovery of 1-hydroxypyridine-2(1H)-thiones-6-carboxylic acid as a low-cytotoxic nanomolar metallo β-lactamase inhibitor

摘要

VIM2 is a carbapenem-hydrolyzing metallo β–lactamase (MBL) found in clinical isolates of ESKAPE pathogens. For drug development, currently, there is a lack of lead compounds with optimal therapeutic potential. Here we report the discovery of 1-hydroxypyridine-2(1H)-thiones-6-carboxylic acid (>3) as a potent VIM2 inhibitor with a Ki of 13 nM and low cytotoxicity CC50 of 97.4 μM. We further showed this inhibitor can restore the antibiotic activity of amoxicillin against VIM-2 producing E. coli in whole cells assays. Its potential mode of binding was examined by molecular modeling and its stability in mouse and human plasma studies was assessed. Overall, >3 exhibits a remarkable 0.99 ligand efficiency against VIM2, a 6,900 fold difference in cytotoxicity from its parent compound and a therapeutic index (TI) of 880, making it a promising lead candidate for combination antibacterial therapy development.