4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-<i>β</i>-Lactamases

• Main Authors: Pasquale Linciano (Author), Eleonora Gianquinto (Author), Martina Montanari (Author), Lorenzo Maso (Author), Pierangelo Bellio (Author), Esmeralda Cebrián-Sastre (Author), Giuseppe Celenza (Author), Jesús Blázquez (Author), Laura Cendron (Author), Francesca Spyrakis (Author), Donatella Tondi (Author)
• Format: Book
• Published: MDPI AG, 2020-03-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available <i>β</i>-lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small library of <i>β</i>-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine <i>β−</i>Lactamase (SBLs) KPC-2 and class B1 metallo <i>β−</i>Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent <i>in silico</i> analyses to elucidate their binding mode within the catalytic pockets of serine- and metallo-BLs. Moreover, several members of the synthesised library have been evaluated, in combination with meropenem (MEM), against clinical strains that overexpress BLs for their ability to synergise carbapenems.

Item Description

1424-8247
10.3390/ph13030052