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4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-?-Lactamases.

ABSTRACT: The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available ?-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 ?-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine ?-Lactamase (SBLs) KPC-2 and class B1 metallo ?-Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent in silico 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.

SUBMITTER: Linciano P 

PROVIDER: S-EPMC7151704 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Linciano Pasquale P   Gianquinto Eleonora E   Montanari Martina M   Maso Lorenzo L   Bellio Pierangelo P   Cebrián-Sastre Esmeralda E   Celenza Giuseppe G   Blázquez Jesús J   Cendron Laura L   Spyrakis Francesca F   Tondi Donatella D  

Pharmaceuticals (Basel, Switzerland) 20200324 3

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>  ...[more]

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