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

VIM‐2 is one of the most common carbapenem‐hydrolyzing metallo β‐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(1 H )‐thione‐6‐carboxylic acid ( 3 ) as a first‐in‐class metallo β‐lactamase inhibitor (MBLi) with a potent inhibition K i 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 EC 50 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 (CC 50 ) of 97 μ m with a corresponding therapeutic index of 880, making it a promising lead candidate for further optimization in combination antibacterial therapy.