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

Authors :
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
Source :
Pharmaceuticals, Vol 16, Iss 12, p 1682 (2023)
Publication Year :
2023
Publisher :
MDPI AG, 2023.

Abstract

The worldwide emergence and dissemination of Gram-negative bacteria expressing metallo-β-lactamases (MBLs) menace the efficacy of all β-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.

Details

Language :
English
ISSN :
14248247
Volume :
16
Issue :
12
Database :
Directory of Open Access Journals
Journal :
Pharmaceuticals
Publication Type :
Academic Journal
Accession number :
edsdoj.36287cbda04f4cacdbee32b86945c1
Document Type :
article
Full Text :
https://doi.org/10.3390/ph16121682