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.
Keywords: Antibacterials, gram-negative bacteria, Kdo, LPS, septic shock, toll-like receptor 4, CD14, lipopolysaccharides, polysaccharide portion, Biochemistry.
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