Design and synthesis of new hydroxyethylamines as inhibitors of D-alanyl-D-lactate ligase (VanA) and D-alanyl-D-alanine ligase (DdlB).
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.
Sova
Matej
M
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.
Cadez
Gasper
G
Turk
Samo
S
Majce
Vita
V
Polanc
Slovenko
S
Batson
Sarah
S
Lloyd
Adrian J
AJ
Roper
David I
DI
Fishwick
Colin W G
CW
Gobec
Stanislav
S
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
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D005021:Ethylamines; C071437:VanA ligase, Bacteria; D019729:Carbon-Oxygen Ligases; D010453:Peptide Synthases; C019638:D-alanylalanine synthetase