Towards the development of novel antibiotics: synthesis and evaluation of a mechanism-based inhibitor of Kdo8P synthase.
The design and two synthetic pathways to aminophosphonate 4 which mimics the ionic and steric properties of putative oxocarbenium intermediate 3 in the Kdo8P synthase-catalyzed reaction are reported. It was found that 4 is a slow-binding, most potent inhibitor of the enzyme yet tested, with a Ki value of 0.4 microM.
Du
S
S
Department of Chemistry and Institute of Catalysis Science and Technology, Technion-Israel Institute of Technology, Haifa.
Faiger
H
H
Belakhov
V
V
Baasov
T
T
D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008070:Lipopolysaccharides / Q000096:biosynthesis; D009682:Magnetic Resonance Spectroscopy; D008353:Mannitol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D013403:Sugar Phosphates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
C405337:1-deoxy-1-((N-(phosphonomethyl)-2-oxoethyl)amino)mannitol-6-phosphate; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D013403:Sugar Phosphates; D008353:Mannitol; C020011:2-dehydro-3-deoxyphosphooctonate aldolase; D000446:Aldehyde-Lyases