Chemoenzymatic synthesis of bacterial nonulosonic acids and glycans

细菌非酮糖酸和聚糖的化学酶法合成

• 批准号: 10364735
• 负责人: Xi Chen
• 金额: $ 30.78万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-05 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364735
• 关键词: Acids; Acinetobacter baumannii; Anabolism; Animals; Antibiotics; Antibodies; Bacteria; Bacterial Infections; Bacterial Polysaccharides; Carbohydrates; Carbon; Chemicals; Complex; Conjugate Vaccines; Development; Enterobacter cloacae; Enzyme Activation; Enzymes; Escherichia coli; Excision; Family; Funding; Future; Generations; Glycoconjugates; Glycosides; Immune system; In Situ; Keto Acids; Libraries; Ligase; Lipopolysaccharides; Mammals; Methods; Monitor; Monosaccharides; Oligosaccharides; Phosphotransferases; Polysaccharides; Process; Production; Propylamines; Proteins; Reaction; Reagent; Research; Role; Sialic Acids; Surface; System; Uridine Diphosphate Galactose; Uridine Diphosphate Sugars; Vertebral column; Vertebrates; Virulence Factors; chemical synthesis; combat; design; glycosylation; glycosyltransferase; host-microbe interactions; improved; inhibitor; pathogenic bacteria; sugar; sugar nucleotide; tool; vaccine candidate

Project Summary Chemoenzymatic synthesis of bacterial nonulosonic acids and glycans Sialic acids are a family of wide-spread nonulosonic acids (alpha-keto acids with a nine-carbon backbone) in vertebrates and in some pathogenic bacteria. Bacteria also produce nonulosonic acids that have not been found in animals. These bacterium-specific nonulosonic acids have been used by bacteria as part of their capsular polysaccharides (CPSs) and lipopolysaccharides (LPSs) which are bacterial virulence factors and potential vaccine candidates. Structurally defined bacterial CPSs, LPSs, and the corresponding oligosaccharide repeating units are important probes to study their roles in bacterial infection and microbe-host interaction including their influence on host immune systems. These carbohydrates are attractive synthetic targets but pose significant synthetic challenges. In addition to bacterial specific nonulosonic acids, they may contain other monosaccharide building blocks that have not been found in mammals. The glycosidic linkages found in bacterial polysaccharides are also much more diverse than those in mammalian glycans. We propose to develop efficient chemoenzymatic methods to synthesize bacterial nonulosonic acids and their glycans as part of CPS and LPS oligosaccharides of pathogenic bacteria. These represent biologically important and synthetically challenging targets. In the current proposal duration, the focus will be on bacterial glycans containing legionaminic acid and their derivatives. Three specific aims are: 1, Synthesize acceptors and monosaccharide chemoenzymatic synthons for one-pot multienzyme (OPME) glycosylation systems; 2, Identify and characterize candidate sugar-1-P kinases, UDP-sugar synthetases, and glycosyltransferases; and 3, Chemoenzymatic synthesis of bacterial polysaccharide repeating units containing legionaminic acid or derivatives. The enzymes identified and the monosaccharides designed are important tools and reagents for accessing synthetic challenging carbohydrates and glycoconjugates that are not limited to the targets described in the proposal. The oligosaccharides produced are essential probes for better understanding the important roles of bacterial polysaccharides. They are also candidates for synthesizing structurally defined carbohydrate-protein conjugate vaccines to combat bacterial infections.

项目摘要 细菌非髓酸和聚糖的化学酶合成 唾液酸是一个广泛非硫酸的家族（α-酮酸，具有九碳主链） 脊椎动物和某些致病细菌。细菌还会产生尚未曾经 在动物中发现。这些细菌特异性非氨基丙酸已被细菌用作其的一部分 囊囊多糖（CPSS）和脂多糖（LPS）是细菌毒力因子和 潜在的疫苗候选物。结构定义的细菌CPS，LPS和相应的 寡糖重复单元是研究其在细菌感染和微生物宿主中作用的重要探针 相互作用，包括它们对宿主免疫系统的影响。这些碳水化合物具有吸引力的合成 目标但构成了重大的合成挑战。除了细菌特异性非氨酸酸外，它们还可以 包含在哺乳动物中未发现的其他单糖构件。糖苷连接 在细菌多糖中发现的也比哺乳动物聚糖的多样性要多样化。我们建议 开发有效的化学酶方法来合成细菌非氨基酸及其聚糖作为 致病细菌的CP和LPS寡糖的一部分。这些代表生物学重要，并且 综合挑战目标。在当前的提案持续时间内，重点将放在细菌聚糖上 含有军团氨酸及其衍生物。三个具体目标是：1，合成受体和 一盘多酶（OPME）糖基化系统的单糖化学合酶合成子； 2，， 识别和表征候选糖-1-p激酶，UDP-糖合成酶和糖基转移酶；和 3，细菌多糖重复单元的化学酶合成，其中含有军团酸或 衍生物。确定的酶和设计的单糖是重要的工具和试剂 获取不限于目标的合成挑战性碳水化合物和糖缀合物 在提案中描述。产生的寡糖是更好地了解 细菌多糖的重要作用。它们也是合成结构定义的候选人 碳水化合物 - 蛋​​白质结合疫苗以对抗细菌感染。