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.
Targeting clinically-relevant metallo-β-lactamases: from high-throughput docking to broad-spectrum inhibitors / Brindisi, Margherita; Brogi, Simone; Giovani, Simone; Gemma, Sandra; Lamponi, Stefania; DE LUCA, Filomena; Novellino, Ettore; Campiani, Giuseppe; Docquier, JEAN DENIS; Butini, Stefania. - In: JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY. - ISSN 1475-6366. - 31:(2016), pp. 98-109. [10.3109/14756366.2016.1172575]
Targeting clinically-relevant metallo-β-lactamases: from high-throughput docking to broad-spectrum inhibitors
BRINDISI, MARGHERITAPrimo
;Novellino, Ettore;
2016
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
