LAUSR

Metallo-β-lactamases (MBLs) are increasingly involved as a major mechanism of resistance to carbapenems in relevant opportunistic Gram-negative pathogens. Unfortunately, clinically efficient MBL inhibitors still represent an unmet medical need .  We previously reported several series of compounds based on the 1,2,4-triazole-3-thione scaffold. In particular, Schiff bases formed between diversely 5-substituted-4-amino compounds and 2-carboxybenzaldehyde were broad-spectrum inhibitors of VIM-type, NDM-1 and IMP-1 MBLs. Unfortunately, they were unable to restore antibiotic susceptibility of MBL-producing bacteria, probably because of poor penetration and/or susceptibility to hydrolysis. To improve their microbiological activity, we developed compounds where the hydrazone-like bond of the Schiff bases was replaced by a stable ethyl link. This small change resulted in a narrower inhibition spectrum, as all compounds were poorly or not inhibiting NDM-1 and IMP-1, but some showed a significantly better activity on VIM-type enzymes, with  K i  values in the μM to sub-μM range. The resolution of the crystallographic structure of VIM-2 in complex with one inhibitor yielded valuable information about their binding mode. Interestingly, several compounds were shown to restore the β-lactam susceptibility of  K. pneumoniae  clinical isolates. In addition, selected compounds were found to be devoid of toxicity toward human cells at high concentration, thus showing promising safety.