BACTERIAL, ENDOTOXIN - MOLECULAR RELATIONSHIPS OF STRUCTURE TO ACTIVITY AND FUNCTION

Endotoxins of Gram-negative microbes fulfill as components of the oute r membrane a vital function for bacterial viability and, if set free, induce in mammalians potent pathophysiological effects. Chemically, th ey are lipopolysaccharides (LPS) consisting of an O-specific chain, a core oligosaccharide, and a lipid component, termed lipid A. The latte r determines the endotoxic activities and, together with the core cons tituent Kdo, essential functions for bacteria. The primary structure o f lipid A of various bacterial origin has been elucidated and lipid A of Escherichia coli has been chemically synthesized. The biological an alysis of synthetic lipid A partial structures proved that the express ion of endotoxic activity depends on a unique primary structure and a peculiar endotoxic conformation. The biological lipid A effects are me diated by macrophage-derived bioactive peptides such as tumor necrosis factor alpha (TNF). Macrophages possess LPS receptors, and the lipid A regions involved in specific binding and cell activation have been c haracterized. Synthetic lipid A partial structures compete the specifi c binding of LPS or lipid A and antagonistically inhibit the productio n of LPS-induced TNF. LPS toxicity, in general, and the ability of LPS to induce TNF are also suppressed by a recently developed monoclonal antibody (IgG2a), which is directed against an epitope located in the core oligosaccharide. At present we determine molecular and submolecul ar details of the specificity of the interaction of lipid A with respo nsive host cells with the ultimate aim to provide pharmacological or i mmunological therapeutics that reduce or abolish the fatal inflammator y consequences of endotoxicosis.