The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available β-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 β-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine β−Lactamase (SBLs) KPC-2 and class B1 metallo β−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.

4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-β-Lactamases / Linciano, Pasquale; Gianquinto, Eleonora; Montanari, Martina; Maso, Lorenzo; Bellio, Pierangelo; Cebrián-Sastre, Esmeralda; Celenza, Giuseppe; Blázquez, Jesús; Cendron, Laura; Spyrakis, Francesca; Tondi, Donatella. - In: PHARMACEUTICALS. - ISSN 1424-8247. - 13:3(2020), pp. 52-67. [10.3390/ph13030052]

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

Linciano, Pasquale
Methodology
;
Tondi, Donatella
Supervision
2020

Abstract

The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available β-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 β-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine β−Lactamase (SBLs) KPC-2 and class B1 metallo β−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.
2020
24-mar-2020
13
3
52
67
4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-β-Lactamases / Linciano, Pasquale; Gianquinto, Eleonora; Montanari, Martina; Maso, Lorenzo; Bellio, Pierangelo; Cebrián-Sastre, Esmeralda; Celenza, Giuseppe; Blázquez, Jesús; Cendron, Laura; Spyrakis, Francesca; Tondi, Donatella. - In: PHARMACEUTICALS. - ISSN 1424-8247. - 13:3(2020), pp. 52-67. [10.3390/ph13030052]
Linciano, Pasquale; Gianquinto, Eleonora; Montanari, Martina; Maso, Lorenzo; Bellio, Pierangelo; Cebrián-Sastre, Esmeralda; Celenza, Giuseppe; Blázquez, Jesús; Cendron, Laura; Spyrakis, Francesca; Tondi, Donatella
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1199566
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