Synthetic Studies of Bacterial Glycans

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The surfaces of bacteria are coated with carbohydrate-containing molecules (glycans) that play critical roles in their life cycles. These glycans are usually essential for life and help protect these organisms from their environment, often modulating the immune system of infected hosts. The pathways by which these carbohy- drates are assembled are potential targets for drug action, and vaccines based on these structures are effective protectants against infection. The ability to chemically synthesize bacterial glycans for use in fundamental chemical and biochemical studies is a necessary prerequisite to achieving these more medically relevant goals. My group has, for several years, studied the synthesis, conformation and biochemistry of glycans from mycobacteria, including Mycobacterium tuberculosis, the organism that causes tuberculosis. Recently, we began a synthetic program on glycans from Campylobacter jejuni, a common cause of food poisoning. We propose here to continue our program on the synthesis of bacterial glycans by focusing on three areas. We will: 1) Expand our synthetic work on campylobacter glycans; 2) Synthesize structurally defined polysaccharides as probes for lipopolysaccharide biosynthesis; 3) Synthesize bradyrhizose, a bicyclic monosaccharide found in rhizobia, and related derivatives. A critical component in all of these projects is the need to develop new synthetic approaches and methodology to address either the unusual structure of the targets or the size of the molecules. Of particular significance, the targets have received little attention from synthetic chemists to date. Our work will be the first in this area and will thus be influential to others working in the field, much like our previous studies of mycobacterial glycan synthesis. This program will provide state-of-the-art training in complex glycan synthesis supported by a program dedicated to the development of independent scientists with a knowledge entrepreneurship and intellectual property. The synthetic work proposed here will lead to molecules for use in studies by collaborators directed at understanding, in greater detail, the assembly and biological role of bacterial glycans.