Glycomimetics of S. aureus CP Aminosugars

描述(由申请人提供)：抗生素耐药性细菌是临床上直接关注的问题，对新的和更有效的治疗方法的需求明显增加。金黄色葡萄球菌是这些微生物中最令人担忧的之一，因为已经发展出的菌株对目前可用的最有效的抗生素如万古霉素都不起作用。由于金黄色葡萄球菌产生一种胶囊多糖(CP)来保护自己免受吞噬，因此攻击用于产生这种聚合物涂层的生化机械应该是一个可行的治疗干预目标。构建多糖的糖基转移酶尚未被分离，因此创造可能抑制酶活性的小分子模拟糖将为酶分离提供工具，以及可能用于抗生素治疗的先导化合物。构成金黄色葡萄球菌荚膜多糖的三种氨基糖是N-乙酰-D-甘露糖醛酸(D-Manaca)、N-乙酰-D-岩藻糖胺和N-乙酰-L-岩藻糖胺。这些糖类中的每一种都将被生产出来。这个建议的具体目标是：1.从叠氮脱氧合成子化学合成N-乙酰基-D-甘露糖醛酸N-糖苷；2.开发我们的二硫杂环丙烷方法来合成碳苷和碳二糖，特别是D-甘露糖类似物；3.制备D-甘露糖的1-脱氧亚胺糖衍生物；4.形成N-乙酰基-D-岩藻糖胺和N-乙酰基-L岩藻糖胺衍生的硝化糖，它们将作为这些化合物的N-和C-糖苷类似物的前体；5.合成金黄色葡萄球菌5型CP中13-D-ManacA-(1，4)-o_-L-FucNAc和8型CP中相应的J3-DmanAcA-(1，3)-α-L-FucNAc连锁酶的三组分潜在抑制剂的合成。

DESCRIPTION (provided by applicant): 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.