Targeting clinically-relevant metallo-β-lactamases: from high-throughput docking to broad-spectrum inhibitors. (1st November 2016)

• Record Type: Journal Article
• Authors: Brindisi, Margherita; Brogi, Simone; Giovani, Simone; Gemma, Sandra; Lamponi, Stefania; De Luca, Filomena; Novellino, Ettore; Campiani, Giuseppe; Docquier, Jean-Denis; Butini, Stefania
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 31(2016 Feb.)Supplement 1
• Page Start: 98
• Page End: 109
• Publication Date: 2016-11-01
• Subjects: Antibiotic resistance -- docking -- metallo-β-lactamase; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.3109/14756366.2016.1172575
• Languages: English
• ISSNs: 1475-6366

Abstract

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 inhibitor3i, which is able to potentiate the in vitro activity of cefoxitin on a VIM-2-producing E. coli strain.