The major goal of this proposal is to delineate the biochemical and enzymological basis of alginate synthesis by Pseudomonas aeruginosa. Alginate is an exopolysaccharide produced by P. aeruginosa during infection in the lungs of cystic fibrosis (CF) patients. Alginate is believed not only to protect the infecting cells from antibiotic therapy and the host immune system but also to facilitate the colonization of the lung through biofilm formation. Alginate is basically synthesized as polymannuronic acid which then undergoes epimerization and acetylation to produce acetylated polymannuronate with varying amounts of guluronate residues in it. Acetylated alginate capsules have been shown to protect the cells from phagocytosis, facilitate biofilm formation and are believed to enhance the survivability of the cells in a dehydrated environment by increasing the water retention property of the capsules. Since exopolysaccharide synthesis, including alginate synthesis, is usually triggered under starvation conditions where the nucleoside triphosphates (such as ATP or GTP) levels are low, and since ATP and GTP are needed continuously because of their involvement in the synthesis of alginate precursors such as fructose 6-phosphate and GDP-mannose, it is important to understand how the synthesis of nucleoside triphosphates in the cells is modulated to provide such cofactors during alginate synthesis. Understanding the biochemical and enzymological basis of alginate synthesis may allow us to screen for or design inhibitors that may have therapeutic potential for the eradication of P. aeruginosa infection from the lungs of CF patients.
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