Re LPS Biogenetic Pathway: Enzyme Characterisation and Synthetic Efforts Towards Inhibitors

Laura      Cipolla; Cristina      Airoldi; Paolo      Galliani; Alessandra      Polissi; Francesco      Nicotra

doi:10.2174/138527208784246003

Abstract

Lipopolysaccharides (LPSs) constitute the lipid portion of the outer leaflet of Gram-negative bacteria; they are essential for growth, and are also responsible for the variety of biological effects associated with Gram-negative sepsis. Recent advances have elucidated the exact chemical structure of this highly complex macromolecule and part of the enzymology involved in its biosynthesis. Enzymes involved in LPS biogenesis are optimal targets for the development of novel therapeutics since they are sufficiently conserved among diverse, clinically-relevant bacteria and no analogue counterpart is present in humans. During the last thirty years a number of inhibitors to LPS biosynthesis have been developed: some of these compounds have antibacterial properties, while others show excellent in vitro activity and are undergoing further investigation. This review will focus on the biology of LPS in bacteria summarizing the knowledge about structure and enzymatic catalysis, as well as chemical efforts towards the synthesis of inhibitors of the key enzymes involved in the biosynthesis of the minimal conserved structure Kdo2-LipA, also referred to as Re LPS. Only a short overview will be given on lipid A biosynthesis and inhibitors, while main focus will be Kdo biosynthesis towards Re LPS. Future directions and perspectives will also be outlined.

Keywords: LpxC Inhibition, Kdo transferases, E. coli, Staphylococcus aureus, phosphoenol pyruvate, Arabinose 5-phosphate Isomerase

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