New targets for antibacterial design: Kdo biosynthesis and LPS machinery transport to the cell surface.

Abstract:

:Lipopolysaccharide (LPS), which constitutes the lipid portion of the outer leaflet of Gram-negative bacteria, is essential for growth. It is 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 much 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 of LPS biosynthesis have been developed: some of these compounds have antibacterial properties, while others show excellent in vitro activity and are undergoing further investigation. The main focus of this review will be 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 Kdo, toward the minimal conserve structure Kdo(2)-LipA. In addition, very recent advances in deciphering the molecular mechanisms of LPS transport to the cell surface, as a new target to develop novel antibacterials, will be reported. Future directions and perspectives will also be outlined.

journal_name

Curr Med Chem

authors

Cipolla L,Polissi A,Airoldi C,Gabrielli L,Merlo S,Nicotra F

doi

10.2174/092986711794927676

subject

Has Abstract

pub_date

2011-01-01 00:00:00

pages

830-52

issue

6

eissn

0929-8673

issn

1875-533X

pii

BSP/CMC/E-Pub/2011/ 048

journal_volume

18

pub_type

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