Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:New targets for antibacterial design: Kdo biosynthesis and LPS machinery transport to the cell surface. 2118 80

Lipopolysaccharides (LPSs), which constitute the lipid portion of the outer leaflet of Gram-negative bacteria, are essential for growth, and are responsible for a variety of biological effects associated with Gram-negative sepsis. LPSs are amphiphilic molecules comprising three regions: lipid A, the core region, and a polysaccharide portion; the lipid A was proven to represent the toxic principle of endotoxic active lipopolysaccharides. In addition, it is known that the minimal conserved structure of LPS is the lipophylic oligoasaccharidic structure containing Kdo residues linked to the-LipA moiety. Thus, the design and development of novel antibacterial drugs can focus on different aspects, related to the biosynthesis and chemical features of LPS: 1) Inhibitors of lipid A biosynthesis 2) Inhibitors of Kdo biosynthesis. Both Kdo and Lipid A are needed for the construction of the minimum structural element Kdo2-LipidA, needed for bacterial survival. Any inhibitors acting on the biogenetic pathway of this molecule can act as antibacterial. 3) Antagonists of the interaction between endotoxins and the host receptors: LPS is recognised by the CD14 and the Toll-like receptor (TLR)-4/MD2 complex, where Lipid A is the crucial moiety in the interaction. Any drug acting as an antagonist of this process can have antisepsis potential. Considerable efforts have been made in this direction to identify natural or synthetic molecules able to interfere with the interaction between LPS and inflammatory cells. This review will highlight recent efforts in the design and biological activity of enzyme inhibitors and antagonist acting on the 3 key aspects outlined above.
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PMID:Recent approaches to novel antibacterials designed after LPS structure and biochemistry. 2287 88