Towards the development of novel antibiotics: synthesis and evaluation of a mechanism-based inhibitor of Kdo8P synthase

Bioorg Med Chem. 1999 Dec;7(12):2671-82. doi: 10.1016/s0968-0896(99)00233-3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aldehyde-Lyases / antagonists & inhibitors*
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Gram-Negative Bacteria / drug effects
  • Gram-Negative Bacteria / metabolism
  • Gram-Negative Bacteria / pathogenicity
  • Hydrogen-Ion Concentration
  • Kinetics
  • Lipopolysaccharides / biosynthesis
  • Magnetic Resonance Spectroscopy
  • Mannitol / analogs & derivatives*
  • Mannitol / chemical synthesis
  • Mannitol / metabolism
  • Mannitol / pharmacology
  • Sugar Phosphates / chemical synthesis*
  • Sugar Phosphates / metabolism
  • Sugar Phosphates / pharmacology*

Substances

  • 1-deoxy-1-((N-(phosphonomethyl)-2-oxoethyl)amino)mannitol-6-phosphate
  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Sugar Phosphates
  • Mannitol
  • 2-dehydro-3-deoxyphosphooctonate aldolase
  • Aldehyde-Lyases