Structural highlights
Function
Q9K2N0_PSEAI
Publication Abstract from PubMed
Zinc ion-dependent beta-lactamases (MBLs) catalyze the hydrolysis of almost all beta-lactam antibiotics and resist the action of clinically available beta-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-beta-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.
In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-beta-lactamase Inhibitors.,Cain R, Brem J, Zollman D, McDonough MA, Johnson RM, Spencer J, Makena A, Abboud MI, Cahill S, Lee SY, McHugh PJ, Schofield CJ, Fishwick CWG J Med Chem. 2018 Jan 10. doi: 10.1021/acs.jmedchem.7b01728. PMID:29271657[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Cain R, Brem J, Zollman D, McDonough MA, Johnson RM, Spencer J, Makena A, Abboud MI, Cahill S, Lee SY, McHugh PJ, Schofield CJ, Fishwick CWG. In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-beta-lactamase Inhibitors. J Med Chem. 2018 Jan 10. doi: 10.1021/acs.jmedchem.7b01728. PMID:29271657 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01728