Design and synthesis of new hydroxyethylamines as inhibitors of d-alanyl- d-lactate ligase (VanA) and d-alanyl- d-alanine ligase (DdlB)

• Published in: Bioorganic & medicinal chemistry letters 2009-03, Vol.19 (5), p.1376-1379
• Main Authors: Sova, Matej, Čadež, Gašper, Turk, Samo, Majce, Vita, Polanc, Slovenko, Batson, Sarah, Lloyd, Adrian J., Roper, David I., Fishwick, Colin W.G., Gobec, Stanislav
• Format: Article
• Language: English
• Subjects: Antibacterial agents; ATP-dependant ligases; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - metabolism; Carbon-Oxygen Ligases - antagonists & inhibitors; Carbon-Oxygen Ligases - metabolism; Crystallography, X-Ray; De novo molecular design; Drug Design; Enterococcus faecium; Enzyme inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Escherichia coli; Ethylamines - chemical synthesis; Ethylamines - pharmacology; Peptide Synthases - antagonists & inhibitors; Peptide Synthases - metabolism; Staphylococcus aureus
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.01.034

The Van enzymes are ATP-dependant ligases responsible for resistance to vancomycin in Staphylococcus aureus and Enteroccoccus species. The de novo molecular design programme SPROUT was used in conjunction with the X-ray crystal structure of Enterococcus faecium d-alanyl- d-lactate ligase (VanA) to design new putative inhibitors based on a hydroxyethylamine template. The two best ranked structures were selected and efficient syntheses developed. The inhibitory activities of these molecules were determined on E. faecium VanA, and due to structural similarity and a common reaction mechanism, also on d-Ala- d-Ala ligase (DdlB) from Escherichia coli. The phosphate group attached to the hydroxyl moiety of the hydroxyethylamine isostere within these systems is essential for their inhibitory activity against both VanA and DdlB.