| Autor: |
Cain, Ricky, Brem, Jürgen, Zollman, David, McDonough, Michael A., Johnson, Rachel M., Spencer, James, Makena, Anne, Abboud, Martine I., Cahill, Samuel, Lee, Sook Y., McHugh, Peter J., Schofield, Christopher J., Fishwick, Colin W. G. |
| Zdroj: |
Journal of Medicinal Chemistry; 20240101, Issue: Preprints |
| Abstrakt: |
Zinc ion-dependent β-lactamases (MBLs) catalyze the hydrolysis of almost all β-lactam antibiotics and resist the action of clinically available β-lactamase inhibitors. We report how application of in silico fragment-based molecular design employing thiol-mediated metal anchorage leads to potent MBL inhibitors. The new inhibitors manifest potent inhibition of clinically important B1 subfamily MBLs, including the widespread NDM-1, IMP-1, and VIM-2 enzymes; with lower potency, some of them also inhibit clinically relevant Class A and D serine-β-lactamases. The inhibitors show selectivity for bacterial MBL enzymes compared to that for human MBL fold nucleases. Cocrystallization of one inhibitor, which shows potentiation of Meropenem activity against MBL-expressing Enterobacteriaceae,with VIM-2 reveals an unexpected binding mode, involving interactions with residues from conserved active site bordering loops. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
