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New Inhibitors of Bacterial and Fungal Cell Wall Biosynthesis


Oligomeric materials consisting of repeat units of carbohydrate monomers frequently represent crucial cell components that are essential for the viability of a whole host of different organisms. For example the mycobacterial cell wall contains several uniq ue carbohydrate structures, such as the arabinogalactan and arabinomannan portions, that do not appear in mammalian biology. It has previously been demonstrated that the correct biosynthesis of these structures is essential for bacterial survival. Therefore inhibition of the biosynthesis of these types of oligosaccharides represents a new and attractive therapeutic strategy against mycobacteria and in particular against tuberculosis. Similarly chitin, which is a (1-4) linked polymer of N-acetylglucosamine, is a major constituent of both fungal cell walls and insect exoskeletons. However chitin also does not appear in mammalian systems, and therefore inhibition of chitin biosynthesis represents a selective strategy for the development of novel fungicides and insecticidal agents.

This research program aims to develop a new strategy for the inhibition of such bacterial and fungal poly- and oligosaccharide biosynthesis by a completely novel mode of action. This research proposal concerns investigations into the feasibility of using this strategy as a method for inhibition of mycobacterial cell wall biosynthesis, and also for the inhibition of fungal cell wall biosynthesis. These studies are designed to investigate the general feasibility of this approach, and hopefully to provide a demonstration of and "proof of concept" for a new approach to the inhibition of oligosaccharide biosynthesis, which may in the near future represent a novel and general therapeutic opportunity against infective organisms, particularly those which have developed resistance to current treatments.

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