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Glycomimetics of S. aureus CP Aminosugars

金黄色葡萄球菌 CP 氨基糖的糖模拟物

基本信息

批准号：
6555616
负责人：
PETER NORRIS
金额：
$ 13.04万
依托单位：
YOUNGSTOWN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-06-01 至 2007-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6555616
关键词：
Staphylococcus aureus aminosugar antibiotics bacterial capsules carbohydrate analog drug design /synthesis /production drug resistance enzyme inhibitors fucose glycosyltransferase mannose microorganism metabolism

项目摘要

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.

描述（由申请人提供）：抗生素耐药性细菌是临床上的一个直接问题，对新的更有效的治疗方法的需求明显且不断增长。金黄色葡萄球菌是这些微生物中最令人担忧的一种，因为已经开发出的菌株即使对目前可用的最有效的抗生素（如万古霉素）也没有反应。自S.金黄色葡萄球菌产生荚膜多糖（CP）以保护自身免受吞噬作用，攻击用于产生这种聚合物涂层的生化机制应该是治疗干预的可行靶点。构建多糖的糖基转移酶尚未被分离，因此产生可能抑制酶活性的小分子糖模拟物将提供用于酶分离的工具，以及用于抗生素治疗的可能的先导化合物。构成最普遍的金黄色葡萄球菌菌株的荚膜多糖的三种氨基糖是N-乙酰基-D-甘露糖糖醛酸（D-ManAcA）、N-乙酰基-D-岩藻糖胺和N-乙酰基-L-岩藻糖胺。将产生这些糖中的每一种的糖模拟物。本提案的具体目标是：1.从叠氮脱氧合成子化学合成N-乙酰基-D-甘露糖糖醛酸N-糖苷; 2.开发我们的二噻烷方法来制备C-糖苷和C-二糖，特别是专注于D-ManAcA类似物; 3. D-ManAcA的1-脱氧亚氨基糖衍生物的制备; 4.形成N-乙酰基-D-岩藻糖胺-和N-乙酰基-L-岩藻糖胺-衍生的硝基糖，其将用作这些化合物的N-和C-糖苷类似物的前体; 5.研究合成用于在金黄色葡萄球菌5型CP中形成1,3-D-ManAcA-（1，4）-o-L-FucNAc键和在8型CP中形成相应的J3-DManAcA-（1，3）-a-L-FucNAc键的酶puronectin的3组分潜在抑制剂。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

N-glycoside neoglycotrimers from 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl azide.

来自 2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖基叠氮化物的 N-糖苷新糖三聚体。

DOI：
10.1016/j.carres.2006.04.011
发表时间：
2006
期刊：
Carbohydrate research.
影响因子：
0
作者：
Temelkoff,DavidP;Zeller,Matthias;Norris,Peter
通讯作者：
Norris,Peter

Application of bis(diphenylphosphino)ethane (DPPE) in Staudinger-type N-glycopyranosyl amide synthesis.

双(二苯基膦)乙烷(DPPE)在Staudinger型N-吡喃葡萄糖酰胺合成中的应用。

DOI：
10.1016/j.carres.2006.02.001
发表时间：
2006
期刊：
Carbohydrate research.
影响因子：
0
作者：
Temelkoff,DavidP;Smith,CraigR;Kibler,DanielA;McKee,Shawn;Duncan,SaraJ;Zeller,Matthias;Hunsen,Mo;Norris,Peter
通讯作者：
Norris,Peter

4-Butyl-1-(2,3,4-tri-O-acetyl-β-l-fuco-pyranos-yl)-1H-1,2,3-triazole.

4-丁基-1-(2,3,4-三-O-乙酰基-β-l-岩藻糖-吡喃基)-1H-1,2,3-三唑。