Endotoxin is the major component of the outer leaflet of Gram-negative bacteria and expresses profound immunstimulatory and inflammatory capacity. The past years have provided new insights into the chemistry and biology of the endotoxin molecule. The knowledge about the submolecular structure of endotoxin, the synthesis of lipid A analogs and the development of endotoxin antagonists have provided an enormous body of information about the process of cellular activation by endotoxin. Furthermore, there was much progress in the knowledge concerning the interplay between endotoxin and soluble or cellular receptors, the signal transduction pathways which are activated by endotoxin, and the cellular responses to endotoxin. However, the precise mechanisms of endotoxin activity in the host turned out to be extremely complex and remain to be completely understood. Nevertheless, the latest advances in understanding the activation of monocytes/macrophages by LPS certainly provide the basis for the future development of novel and hopefully better strategies in the fight against Gram-negative infections.

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Lipopolysaccharides (LPS) are the major outer surface membrane components expressed by the vast majority of Gram-negative bacteria and have been identified to be extremely strong stimulators of innate or natural immunity in diverse eukaryotic species ranging from insects or plants to humans. Due to early observations on the induction of severe pathological forms of immunoactivation such as septic shock this class of bacterial surface molecules has been termed ‘endotoxins’. By combination of chemical analysis, mass spectrometry and NMR techniques, the chemical structures of LPS from a variety of Gram-negative bacteria have been characterized in detail. LPS consist of an extracellular poly- or oligosaccharide region that is anchored in the outer bacterial membrane by a specific glycolipid termed lipid A. The lipid A component has been identified to be the primary immunostimulatory center of LPS. An overview of major types of lipid A structures recently established is given, thus completing and updating previous reviews (1, 2). In the present review central structure-bioactivity-correlations are discussed with respect to immunoactivation of the mammalian phagocyte system. In addition to the classical group of strongly agonistic (highly endotoxic) forms of lipid A, several natural or synthetic lipid A structures have been identified that display comparatively low or even no phagocyte activation for a given mammalian species. Some members of the latter more heterogeneous group are capable to antagonize the effects of strongly stimulatory LPS/lipid A. LPS of Gram-negative bacteria have been found to express a certain degree of structural diversity with respect to three structural elements: the glycosyl part of lipid A (lipid A backbone), the number, charge and linkage of polar head-group substituents, and the number, position and chemical nature of various acyl residues directly or indirectly linked to the lipid A backbone. Among all these structural variations, the acylation pattern has been found to encode mostly for its strong agonistic or antagonistic immunostimulatory activities in various biosystems.

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Lipopolysaccharides (LPS) are the endotoxins of Gram-negative bacteria and very well known for their immunological, pharmacological and pathophysiological effects displayed in eucaryotic cells and organisms. To date, much emphasis has been put on the elucidation of the chemical structures of LPS and on their relation, or that of substructures, to the various biological effects. The lipid part of LPS, the lipid A, was proven to represent the toxic principle of endotoxin. However, lipid A toxicity depends strongly on its structure, and is influenced by a second region of LPS, the core region, that is covalently linked to lipid A. Also, the core region possesses immunogenic properties. Therefore, complete structural analyses of the core region and the comparison of its structures with biological features of LPS are of high importance for a better understanding of LPS action, and one prerequesite for strategies aimed at the treatment of endotoxicosis. In the past, quite a number of structures of the core regions from various Gram-negative bacteria were published and summarized in several overviews. The present review adds to this knowledge those structures that were published between October 1998 and December 2001.

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In humans, various peptic diseases and ailments are attributed to infection by the Gram-negative bacterium, Helicobacter pylori. Among the various pathogenic factors of H. pylori, the lipopolysaccharides (LPS) display two different characteristics to LPS of other Gram-negative bacteria. These include low biological activity and the presence of structures similar to human blood Lewis antigens. The former is derived from H. pylori lipid A structure that contains long fatty acids (βOHC₁₈, βOHC₁₆ and C₁₆) and is deficient in the phosphate group at the non-reducing end of glucosamine disaccharide, compared to the lipid A structure of Escherichia coli. Epitopes similar to the Lewis antigen structure are present in the non-reducing end unit of the O-polysaccharide moiety, which may lead to the adhesion and colonization of this bacterium with human gastric epithelial cells. Recently, epitopes distinct from Lewis related antigens were identified in the O-polysaccharide moiety. These novel epitopes appear to be associated with peptic disease.

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We have developed an efficient synthetic pathway for lipid A and its glycosylation method with Kdo. In combination with several additional new ideas such as the use of an oxidation-resistant benzyl-type protecting group and the application of liquid-liquid partition column chromatography, the synthesis of Re-type lipopolysaccharide has been achieved for the first time. The pathway allows us to synthesize various structural congeners of lipopolysaccharide of high purity, which are necessary to evaluate the biological and physicochemical functions of lipopolysaccharide precisely.

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