Discovery of 1-Hydroxypyridine-2(1H)-thione-6-carboxylic Acid as a First-in-Class Low-Cytotoxic Nanomolar Metallo ?-Lactamase Inhibitor.

ABSTRACT: VIM-2 is one of the most common carbapenem-hydrolyzing metallo ?-lactamases (MBL) found in many drug-resistant Gram-negative bacterial strains. Currently, there is a lack of effective lead compounds with optimal therapeutic potential within our drug development pipeline. Here we report the discovery of 1-hydroxypyridine-2(1H)-thione-6-carboxylic acid (3) as a first-in-class metallo ?-lactamase inhibitor (MBLi) with a potent inhibition Ki of 13?nm against VIM-2 that corresponds to a remarkable 0.99 ligand efficiency. We further established that 3 can restore the antibiotic activity of amoxicillin against VIM-2-producing E. coli in a whole cell assay with an EC50 of 110?nm. The potential mode of binding of 3 from molecular modeling provided structural insights that could corroborate the observed changes in the biochemical activities. Finally, 3 possesses a low cytotoxicity (CC50 ) of 97??m with a corresponding therapeutic index of 880, making it a promising lead candidate for further optimization in combination antibacterial therapy.

SUBMITTER: Shin WS 

PROVIDER: S-EPMC6034706 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature