Synthesis and evaluation of a mechanism-based inhibitor of KDO8P synthase Original Research Article

The enzyme 3-deoxy-d-manno-2-octulosonate-8-phosphate (KDO8P) synthase catalyzes the condensation reaction between phosphoenolpyruvate (PEP) and d-arabinose 5-phosphate (A5P) to produce KDO8P and inorganic phosphate. In attempts to investigate the lack of antibacterial activity of the most potent inhibitor of KDO8P synthase, the amino phosphonophosphate , we have synthesized its hydrolytically stable isosteric phosphonate analogue and tested it as an inhibitor of the enzyme. The synthesis of was accomplished in a one step procedure by employing the direct reductive amination in aqueous media between unprotected sugar phosphonate and glyphosate. The analogue proved to be a competitive inhibitor of KDO8P synthase with respect to both substrates A5P and PEP binding. In vitro antibacterial tests against a series of different Gram-negative organisms establish that both inhibitors ( and ) lack antibacterial activity probably due to their reduced ability to penetrate the bacterial cell membrane.