| Affiliation: | 1. Dipartimento di Biotecnologie Mediche, Università di Siena, 53100 Siena, Italy
These authors contributed equally to this work.;2. IBMM, CNRS, Univ Montpellier, ENSCM, Montpellier, France;3. Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, 53100 Siena, Italy;4. Dipartimento di Biotecnologie Mediche, Università di Siena, 53100 Siena, Italy;5. Laboratoire de Biochimie, Centre?d'Ingénierie des Protéines-InBioS, Université de Liège, Allée du 6 août B6, Sart-Tilman, 4000 Liège, Belgium;6. Laboratoire des Macromolécules Biologiques, Centre?d'Ingénierie des Protéines-InBioS, Université de Liège, Institute of Chemistry B6a, Sart-Tilman, 4000 Liège, Belgium;7. HSM, Univ Montpellier, CNRS, IRD, CHU Montpellier, Montpellier, France |
| Abstract: | 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, these compounds 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 synthesized and characterized compounds where the hydrazone-like bond of the Schiff base analogues 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 showed a significantly better activity on VIM-type enzymes, with Ki values in the μM to sub-μM range. The resolution of the crystallographic structure of VIM-2 in complex with one of the best inhibitors yielded valuable information about their binding mode. Interestingly, several compounds were shown to restore the β-lactam susceptibility of VIM-type-producing E. coli laboratory strains and also of K. pneumoniae clinical isolates. In addition, selected compounds were found to be devoid of toxicity toward human cancer cells at high concentration, thus showing promising safety. |
