Glycomimetics of S. aureus CP Aminosugars

Norris, Peter

Abstract

Antibiotic resistant bacteria are an immediate concern in the clinic and there is an obvious and growing need for new and more effective treatments. Staphylococcus aureus is one of the most worrying of these microorganisms since strains have developed that do not respond to even the most potent antibiotics currently available such as vancomycin. Since S. aureus produces a capsular polysaccharide (CP) to protect itself from phagocytosis, attacking the biochemical machinery that is used to create this polymeric coating should be a viable target for therapeutic intervention. The glycosyl transferase enzymes that build the polysaccharides have yet to be isolated therefore creating small molecule glycomimetics that might inhibit enzymatic activity will provide tools for enzyme isolation, as well as possible lead compounds for antibiotic treatment. The three amino sugars that make up the capsular polysaccharides of the most prevalent strains of S.aureus are N-acetyI-D-mannose uronic acid (D-ManAcA), N-acetyI-D-fucosamine and N-acetyI-L-fucosamine. Glycomimetics of each of these sugars will be produced. The specific goals of this proposal are:1. Chemical synthesis of N-acetyI-D-mannose uronic acid N-glycosides from an azidodeoxy synthon; 2. Development of our dithiane approach to C-glycosides and C-disaccharides, especially focusing on D-ManAcA analogs; 3. Preparation of 1-deoxy iminosugar derivatives of D-ManAcA; 4. Formation of N-acetyI-D-fucosamine- and N-acetyI-L-fucosamine-derived nitroglycals that will serve as precursors to both N- and C-glycoside analogs of these compounds; 5. Studies towards the synthesis of 3-component potential inhibitors of the enzymes putatively used to form the 13-D-ManAcA- (1,4)-o_-L-FucNAc linkage in S.aureus type 5 CP and the corresponding J3-DManAcA-(1,3)-alpha-L-FucNAc linkage in the type 8 CP.