1. 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
- Author
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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, and Donatella Tondi
- Subjects
1,2,4-triazole-3-thione ,structure-based drug design ,NDM-1 ,competitive inhibitors ,resistance ,Medicine ,Pharmacy and materia medica ,RS1-441 - 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.
- Published
- 2023
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