Lipopolysaccharides (LPSs) are unique amphipathic molecules that make up the outer surface of the outer membranes of gram-negative bacteria, including those of many pathogens. Because of the extraordinary difficulties encountered in working with these substances, the exact covalent structure of the hydrophobic anchor of LPS (termed lipid A) was unknown prior to 1983. A complete understanding of the structure, biosynthesis and function of lipid A is very important, because lipid A is the active component of LPS responsible for many of the clinical complications of gram-negative sepsis. For this reason lipid A is also known as endotoxin. Despite the important role of lipid A in the pathophysiology of gram- negative infections, relatively little is known about the biochemistry, molecular biology and regulation of lipid A synthesis. Significant progress in this field was made possible by the P.I's. discovery of monosaccharide lipid A precursors in ceriain phosphatidylglycerol- deficient mutants of Escherichia coli. It is now firmly established that lipid A is essential for the growth of gram-negative bacteria and that inhibitors of lipid A biosynthesis could be novel antibiotics. In addition, Certain precursors of lipid A are antagonists of the action of lipid A as an endotoxin, and they may be prototypes for new pharmacological agents useful in the treatment of endotoxin-induced shock. Since 1983, the P.I's. objective has been to define the biosynthesis of lipid A at the level of enzymology and molecular genetics. The enzymes of lipid A synthesis are useful for the preparation of novel biochemical probes with which to study the interaction of endotoxins and animal cells. In the coming grant period the specific aims will be: l) the elucidation of regulatory mechanisms that control lipid A biosynthesis in E. coli; 2) the isolation of new mutants defective in the later enzymatic steps of the lipid A pathway; 3) the determination of the molecular basis for LPS export from its site of biosynthesis in the cytoplasm to the outer membrane; and 4) the exploration of the function of lipid A in E. coli membranes using biochemical and genetic strategies.
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