title: Design and synthesis of new hydroxyethylamines as inhibitors of D-alanyl-D-lactate ligase (VanA) and D-alanyl-D-alanine ligase (DdlB).
abstract: 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 faeciumd-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.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.
authors.forename: Matej
authors.initials: M
authors.lastname: Sova
authors.forename: Gasper
authors.initials: G
authors.lastname: Cadez
authors.forename: Samo
authors.initials: S
authors.lastname: Turk
authors.forename: Vita
authors.initials: V
authors.lastname: Majce
authors.forename: Slovenko
authors.initials: S
authors.lastname: Polanc
authors.forename: Sarah
authors.initials: S
authors.lastname: Batson
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Lloyd
authors.forename: David I
authors.initials: DI
authors.lastname: Roper
authors.forename: Colin W G
authors.initials: CW
authors.lastname: Fishwick
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019729:Carbon-Oxygen Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005021:Ethylamines / Q000138:chemical synthesis* / Q000494:pharmacology; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D005021:Ethylamines; C071437:VanA ligase, Bacteria; D019729:Carbon-Oxygen Ligases; D010453:Peptide Synthases; C019638:D-alanylalanine synthetase