Functional and structural identification of peptidoglycan part structures involved in thrombospondin-1 mediated adherence of Gram-positive bacteria to host cells

参与血小板反应蛋白-1介导的革兰氏阳性菌与宿主细胞粘附的肽聚糖部分结构的功能和结构鉴定

• 批准号: 64038601
• 负责人: Professor Dr. Sven Hammerschmidt
• 金额: --
• 依托单位: Forschungsgruppe Bioanalytische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/64038601?language=en
• 关键词: Functional; structural; identification; peptidoglycan; part

Peptidoglycan (PG, murein) is an essential exoskeleton needed to withstand the internal cytoplasmic turgor (osmotic) pressure in both Gram-negative as well as Gram-positive bacteria. It consists of oligo-(GlcNAc-MurNAc)glycan strands that are cross-linked by short peptides to form a complex three-dimensional scaffold (murein) that surrounds and stabilizes the bacterial cytoplasmic membrane. Studies in our laboratory show that Gram-positive bacteria such as Streptococcus pneumoniae, S. pyogenes and Staphylococcus aureus engage the human glycoprotein and lectin thrombospondin-1 (TSP-1) as a molecular sensor, thereby promoting adherence of the bacteria to host cells. We could demonstrate that purified soluble PG natural part structures from S. aureus inhibits TSP-1 mediated Gram-positive bacterial adherence, indicating that TSP-1 recognizes the PG of the bacteria. Based on these data we plan to explore the role of PG structures for TSP-1 mediated interactions on the basis of a structure-function relationship in more detail. In our planned studies we will combine the capacity of synthetic chemistry, analytical and structural chemistry and biochemical/immunological studies to explore the minimal PG part structure which shows bioactivity in TSP-1 mediated adherence of bacteria to host cells. We will use purified and completely analyzed natural PG moieties as well as synthetic PG moieties and according to the biological activity chemically modified PG structures in our infection assays. It is anticipated that the combination of purified PG structures on the one side as well as functionally designed synthetic PG part structures will provide new insights into the biological function of PG. On a long term goal it is expected that these findings have an impact for the development of newer strategies against colonization by Gram-positive bacteria and will finally lead to newer strategies against Gram-positive sepsis.

肽聚糖（PG，胞壁素）是革兰氏阴性菌和革兰氏阳性菌中抵抗内部细胞质膨压（渗透压）所需的基本外骨骼。它由寡聚-（GlcNAc-MurNAc）聚糖链组成，这些聚糖链通过短肽交联以形成复杂的三维支架（胞壁蛋白），该支架包围并稳定细菌细胞质膜。本实验室的研究表明，革兰氏阳性菌如肺炎链球菌、S。化脓性链球菌和金黄色葡萄球菌结合人糖蛋白和凝集素血小板反应蛋白-1（TSP-1）作为分子传感器，从而促进细菌与宿主细胞的粘附。我们可以证明，纯化的可溶性PG天然部分结构从S。金黄色葡萄球菌抑制TSP-1介导的革兰氏阳性细菌粘附，表明TSP-1识别细菌的PG。基于这些数据，我们计划探索PG结构的TSP-1介导的相互作用的基础上，更详细的结构-功能关系的作用。在我们计划的研究中，我们将联合收割机结合合成化学、分析和结构化学以及生物化学/免疫学研究的能力，以探索在TSP-1介导的细菌粘附至宿主细胞中显示生物活性的最小PG部分结构。我们将使用纯化的和完全分析的天然PG部分以及合成的PG部分，并根据我们的感染测定中的生物活性化学修饰的PG结构。预计一方面纯化PG结构和功能性设计的合成PG部分结构的组合将为PG的生物学功能提供新的见解。在长期目标上，预计这些发现对革兰氏阳性菌定植的新策略的发展产生影响，并最终导致革兰氏阳性脓毒症的新策略。