TY - JOUR
T1 - In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors
AU - Cain, Ricky
AU - Brem, Jürgen
AU - Zollman, David
AU - McDonough, Michael A.
AU - Johnson, Rachel M.
AU - Spencer, James
AU - Makena, Anne
AU - Abboud, Martine I.
AU - Cahill, Samuel
AU - Lee, Sook Y.
AU - McHugh, Peter J.
AU - Schofield, Christopher J.
AU - Fishwick, Colin W.G.
PY - 2018/2/8
Y1 - 2018/2/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85042121524&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.7b01728
DO - 10.1021/acs.jmedchem.7b01728
M3 - Article (Academic Journal)
C2 - 29271657
AN - SCOPUS:85042121524
VL - 61
SP - 1255
EP - 1260
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 3
ER -