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Structure-Based Optimization of 1,2,4-Triazole-3-Thione Derivatives: Improving Inhibition of NDM-/VIM-Type Metallo-beta -Lactamases and Synergistic Activity on Resistant Bacteria

Articolo
Data di Pubblicazione:
2023
Abstract:
The worldwide emergence and dissemination of Gram-negative bacteria expressing metallo-beta-lactamases (MBLs) menace the efficacy of all beta -lactam antibiotics, including carbapenems, a last line treatment usually restricted to severe pneumonia and urinary tract infections. Nonetheless, no MBL inhibitor is yet available in therapy. We previously identified a series of 1,2,4-triazole-3-thione derivatives acting as micromolar inhibitors of MBLs in vitro, but devoid of synergistic activity in microbiological assays. Here, via a multidisciplinary approach, including molecular modelling, synthesis, enzymology, microbiology, and X-ray crystallography, we optimized this series of compounds and identified low micromolar inhibitors active against clinically relevant MBLs (NDM-1- and VIM-type). The best inhibitors increased, to a certain extent, the susceptibility of NDM- 1- and VIM-4-producing clinical isolates to meropenem. X-ray structures of three selected inhibitors in complex with NDM-1 elucidated molecular recognition at the base of potency improvement, confirmed in silico predicted orientation, and will guide further development steps.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
1,2,4-triazole-3-thione, structure-based drug design, NDM-1, competitive inhibitors, resistance
Elenco autori:
Matteo Bersani; Mariacristina Failla; Filippo Vascon; Eleonora Gianquinto; Laura Bertarini; Massimo Baroni; Gabriele Cruciani; Federica Verdirosa; Filomena Sannio; Jean-Denis Docquier; Laura Cendron; Francesca Spyrakis; Loretta Lazzarato; Donatella Tondi
Autori di Ateneo:
BERSANI MATTEO
GIANQUINTO Eleonora
LAZZARATO Loretta
SPYRAKIS Francesca
Link alla scheda completa:
https://iris.unito.it/handle/2318/1946126
Link al Full Text:
https://iris.unito.it/retrieve/handle/2318/1946126/1215477/2023_triazoli_pharmaceuticals.pdf
Pubblicato in:
PHARMACEUTICALS
Journal
Progetto:
LAZZARATO L. - Contrib. Fondazione CRT II tornata 2019 RF. 2019.2258 - "Resistenza antimicrobica..." - Cdd 28/02/2020
  • Dati Generali
  • Aree Di Ricerca

Dati Generali

URL

https://www.mdpi.com/1424-8247/16/12/1682

Aree Di Ricerca

Settori (14)


LS6_9 - Antimicrobials, antimicrobial resistance - (2022)

PE5_18 - Medicinal chemistry - (2022)

CIBO, AGRICOLTURA e ALLEVAMENTI - Farmacologia Veterinaria

CIBO, AGRICOLTURA e ALLEVAMENTI - Patologia e malattie degli animali

CIBO, AGRICOLTURA e ALLEVAMENTI - Scienze cliniche veterinarie

MEDICINA, SALUTE e BENESSERE - Chimica e Salute

MEDICINA, SALUTE e BENESSERE - Epidemiologia

MEDICINA, SALUTE e BENESSERE - Oncologia e Tumori

MEDICINA, SALUTE e BENESSERE - Ricerca Traslazionale e Clinica

MEDICINA, SALUTE e BENESSERE - Trapianti e medicina rigenerativa

PIANETA TERRA, AMBIENTE, CLIMA, ENERGIA e SOSTENIBILITA' - Chimica e Ambiente

SCIENZE DELLA VITA e FARMACOLOGIA - Chimica Analitica e Farmaceutica

SCIENZE DELLA VITA e FARMACOLOGIA - Interazioni tra molecole, cellule, organismi e ambiente

SCIENZE MATEMATICHE, CHIMICHE, FISICHE - Materiali Avanzati
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