Synthesis and antibacterial activity of mechanism-based inhibitors of KDO8P synthase and DAH7P synthase.
KDO8PS (3-deoxy-D-manno-2-octulosonate-8-phosphate synthase) and DAH7PS (3-deoxy-D-arabino-2-heptulosonate-7-phosphate synthase) are attractive targets for the development of new anti-infectious agents. Both enzymes appear to proceed via a common mechanism involving the reaction of phosphoenolpyruvate (PEP) with arabinose 5-phosphate or erythrose-4-phosphate, to produce the corresponding ulosonic acids, KDO8P and DAH7P, respectively. The synthesis of new inhibitors closely related to the supposed tetrahedral intermediate substrates for the enzymes is described. The examination of the antibacterial activity of these derivatives is reported.
Grison
Claude
C
Laboratoire de Chimie Organique Biomoléculaire, UMR CNRS 7565, Institut Nancéien de Chimie Moléculaire, Université Henri Poincaré, Nancy 1, BP 239, F-54506 Vandoeuvre-lès-Nancy, France. cgrison@univ-montp2.fr
Petek
Sylvain
S
Finance
Chantal
C
Coutrot
Philippe
P
D010723:3-Deoxy-7-Phosphoheptulonate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002384:Catalysis; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D013058:Mass Spectrometry; D015394:Molecular Structure; D010428:Pentosephosphates / Q000378:metabolism; D010728:Phosphoenolpyruvate / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013403:Sugar Phosphates / Q000378:metabolism
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D010428:Pentosephosphates; D013403:Sugar Phosphates; C028055:arabinose 5-phosphate; C026959:erythrose 4-phosphate; D010728:Phosphoenolpyruvate; D010723:3-Deoxy-7-Phosphoheptulonate Synthase; C020011:2-dehydro-3-deoxyphosphooctonate aldolase; D000446:Aldehyde-Lyases