Back to Search
Start Over
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
- 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