Chemoenzymatic synthesis of bacterial nonulosonic acids and glycans

细菌非酮糖酸和聚糖的化学酶法合成

基本信息

批准号：
10186358
负责人：
Xi Chen
金额：
$ 30.91万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/10186358
关键词：
Acids Acinetobacter baumannii Anabolism Animals Antibiotics Antibodies Bacteria Bacterial Infections Bacterial Polysaccharides Biological 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 Structure Surface System Uridine Diphosphate Galactose Uridine Diphosphate Sugars Vertebral column Vertebrates Virulence Factors chemical synthesis combat design glycosylation glycosyltransferase host-microbe interactions improved inhibitor/antagonist pathogenic bacteria sugar sugar nucleotide tool vaccine candidate

项目摘要

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.

项目概要细菌非酮糖酸和聚糖的化学酶法合成唾液酸是广泛分布的非糖酸家族（具有九个碳主链的α-酮酸）脊椎动物和一些致病细菌。细菌还产生非酮糖酸，这些酸未被在动物中发现。这些细菌特异性的非酮糖酸已被细菌用作其细菌的一部分。荚膜多糖（CPS）和脂多糖（LPS）是细菌毒力因子潜在的候选疫苗。结构明确的细菌 CPS、LPS 以及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。这些碳水化合物是有吸引力的合成物目标，但提出了重大的综合挑战。除了细菌特异性的非酮糖酸外，它们还可能含有在哺乳动物中未发现的其他单糖结构单元。糖苷键细菌多糖中发现的多糖也比哺乳动物多糖更加多样化。我们建议开发有效的化学酶方法来合成细菌非糖酸及其聚糖病原菌的CPS和LPS寡糖的一部分。这些代表了生物学上的重要性和具有综合挑战性的目标。在当前提案期间，重点将放在细菌聚糖上含有军团胺酸及其衍生物。三个具体目标是：1、合成受体和用于一锅多酶（OPME）糖基化系统的单糖化学酶合成子； 2、鉴定和表征候选糖-1-P激酶、UDP-糖合成酶和糖基转移酶；和 3、化学酶法合成含有军团氨基酸或细菌多糖重复单元衍生物。鉴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具有挑战性的碳水化合物和糖复合物提案中描述。产生的寡糖是更好地了解寡糖的必要探针细菌多糖的重要作用。它们也是合成结构定义的候选物碳水化合物-蛋白质结合疫苗可对抗细菌感染。