In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors

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.