Targeting clinically-relevant metallo-β-lactamases: from high-throughput docking to broad-spectrum inhibitors

摘要

Metallo-β-lactamases (MBLs) represent one of the most important and widespread mechanisms of resistance to β-lactam antibiotics (including the life-saving carbapenems), against which no clinically useful inhibitors are currently available. We report herein a structure-based high-throughput docking (HTD) campaign on three clinically-relevant acquired MBLs (IMP-1, NDM-1 and VIM-2). The initial hit NF1810 (1) was optimized providing the broad-spectrum inhibitor 3i, which is able to potentiate the in vitro activity of cefoxitin on a VIM-2-producing E. coli strain.