Discovery Of 1-Hydroxypyridine-2(1h)-Thione-6-Carboxylic Acid As A First-In-Class Low-Cytotoxic Nanomolar Metallo -Lactamase Inhibitor

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 K-i of 13nm 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 110nm. 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 97m with a corresponding therapeutic index of 880, making it a promising lead candidate for further optimization in combination antibacterial therapy.