Abstract
Endotoxins, chemically lipopolysaccharides (LPS), are major components of the cell envelope of Gram-negative bacteria which are an important contributing factor to septic shock, in general, and Gram-negative septic shock, in particular. The structure of the lipid moiety of LPS, lipid A, has been intensively investigated in Escherichia coli and Salmonella spp. and based on the structural data, synthetic compounds prepared. In general, these compounds exhibit identical endotoxic activities compared with bacterial lipid A and LPS, thus confirming that lipid A is the endotoxic center of LPS. Analysis of lipid A from various Gram-negative bacterial species showed that lipid A is a family of (phospho)glycolipid molecules that are closely related in general architecture, but whose fine structure varies. The various structures of selected lipid As of different bacterial species are reviewed in this article and the influence of their structure on endotoxicity is discussed. The resulting Deductions on structure-bioactivity relationships from the latter studies is supported and extended by investigations on the bioactivity (endotoxicity) of synthetic lipid A analogs and partial structures. In particular, endotoxicity is not dependent on one lipid A constituent, i.e., a toxophore group, but it is a unique molecular structure, a peculiar surpramolecular conformation, which allows optimal expression of endotoxicity activity. Furthermore, LPS is not a direct toxin, rather endotoxic shock is a syndrome that results from the host's own response to LPS whereby there is systemic release of endogenous substances (cytokines) that control the cascade of events leading to shock. Considerable advances have been made in understanding the specific interaction of endotoxin with serum proteins and monocyte/macrophage-bound recognition molecules. Since this is the central event of endotoxin activity leading to endotoxic shock, therapeutic approaches have been proposed blocking this event.