Citric acid cycle regulation of exopolysaccharide synthesis in staphylococci

葡萄球菌胞外多糖合成的柠檬酸循环调节

基本信息

批准号：
7860186
负责人：
GREG Alan SOMERVILLE
金额：
$ 35.46万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7860186
关键词：
Aconitate Hydratase Address Adhesions Affect Affinity Amino Sugars Anabolism Analytical Chemistry Animal Diseases Antibiotics Archives Bacteria Bacterial Infections Binding Biochemistry Bioinformatics Catechols Citric Acid Cycle Code Complex DNA Binding DNA Binding Domain Dinucleoside Phosphates Dioxygenases Electrophoretic Mobility Shift Assay Environment Escherichia coli Ethanol Genetic Genetic Transcription Genome Genus staphylococcus Glucosamine Glutamine Goals Heating Hospitals Host Defense Human Immune Immune system Immunoblotting Infection Iron Lead Literature Measures Mediating Mediator of activation protein Metabolic Metabolism Microbial Biofilms Molecular Biology Morbidity - disease rate Mutation NADH Nickel Northern Blotting Nutrient Oxygen Patients Phagocytosis Physicians Plasmids Polysaccharides Predisposition Promoter Regions Property Proteins PubMed Publishing Regulation Reporter Research Resources Shock Signal Transduction Signal Transduction Pathway Staphylococcal Infections Staphylococcus aureus Staphylococcus epidermidis Stimulus Stress Surface Systems Biology Testing Therapeutic Thick Translating Treatment Cost Tricarboxylic Acids United States Virulence Work aminobutyrate base biological adaptation to stress capsule design environmental change expression vector gene cloning genetic regulatory protein killings metabolomics mutant novel pathogen polysaccharide intercellular adhesin prevent public health relevance response sugar

项目摘要

DESCRIPTION (provided by applicant): Staphylococcus aureus and Staphylococcus epidermidis are opportunistic bacterial pathogens responsible for a wide array of human and animal diseases. Importantly, S. aureus and S. epidermidis are the two leading causes of hospital-associated infections, which significantly increase morbidity and treatment costs. Exopolysaccharides are important mediators of staphylococcal infections; specifically, polysaccharide intercellular adhesin (PIA) enhances biofilm formation and immune evasion, while capsule facilitates immune evasion, colonization, and persistence. Staphylococcal PIA is synthesized when tricarboxylic acid (TCA) cycle activity is repressed. In contrast, synthesis of the S. aureus capsular polysaccharide requires TCA cycle activity. Interestingly, PIA and capsule are derived from the same amino sugar (i.e., UDP-N-acetyl-glucosamine. Synthesis of both exopolysaccharides is modulated by the availability of nutrients, oxygen, and iron. Similarly, TCA cycle activity is regulated by the availability of nutrients, oxygen, and iron and by certain stress-inducing stimuli such as heat, ethanol, and antibiotics. The linkage of TCA cycle activity and exopolysaccharide synthesis and the susceptibility of the TCA cycle to environmental inactivation lead us to hypothesize that one mechanism by which staphylococci perceive external environmental change is through alterations in TCA cycle activity. These changes in TCA cycle activity alter the bacterial metabolome increasing or decreasing the intracellular concentrations of metabolites and co- factors that are "sensed" by regulatory proteins, which increase or decrease exopolysaccharide biosynthesis. The aims of this proposal are to identify the TCA cycle metabolites that control exopolysaccharide synthesis and determine which regulatory proteins are responding to these TCA cycle metabolites to regulate exopolysaccharide synthesis. To achieve these aims, we will use an integrated approach combining systems biology, biochemistry, bioinformatics, and genetics. The rationale for the proposed research is to fill the gap in our understanding of how environmental conditions affect the bacterial metabolic status and, in turn, how the metabolic status affects staphylococcal exopolysaccharide biosynthesis. Understanding this will aid in our long-term goal, which is to design therapeutic strategies targeting staphylococcal metabolism and metabolic responsive regulators that will facilitate bacterial killing by antibiotics and the host immune system.

描述（由申请人提供）：金黄色葡萄球菌和表皮葡萄球菌是导致多种人类和动物疾病的机会性细菌病原体。重要的是，金黄色葡萄球菌和表皮葡萄球菌是医院相关感染的两个主要原因，这显着增加了发病率和治疗成本。胞外多糖是葡萄球菌感染的重要介质；具体来说，多糖细胞间粘附素（PIA）增强生物膜形成和免疫逃避，而胶囊则促进免疫逃避、定植和持久性。当三羧酸 (TCA) 循环活性受到抑制时，葡萄球菌 PIA 就会合成。相反，金黄色葡萄球菌荚膜多糖的合成需要TCA循环活性。有趣的是，PIA 和胶囊源自相同的氨基糖（即 UDP-N-乙酰基-葡萄糖胺）。两种胞外多糖的合成均受营养物、氧气和铁的可用性调节。同样，TCA 循环活性受可用性调节营养物、氧气和铁以及某些应激诱导刺激（例如热、乙醇和抗生素）的 TCA 循环活性和胞外多糖合成的联系以及对细胞的敏感性。 TCA 循环导致环境失活使我们假设葡萄球菌感知外部环境变化的一种机制是通过 TCA 循环活性的改变来改变细菌代谢组，从而增加或减少细胞内代谢物和辅因子的浓度。被调节蛋白“感知”，从而增加或减少胞外多糖生物合成。该提案的目的是鉴定控制胞外多糖合成的TCA循环代谢物并确定哪些调节蛋白。响应这些 TCA 循环代谢物来调节胞外多糖合成。为了实现这些目标，我们将采用结合系统生物学、生物化学、生物信息学和遗传学的综合方法。拟议研究的基本原理是填补我们对环境条件如何影响细菌代谢状态以及代谢状态如何影响葡萄球菌胞外多糖生物合成的理解空白。了解这一点将有助于我们的长期目标，即设计针对葡萄球菌代谢和代谢反应调节剂的治疗策略，以促进抗生素和宿主免疫系统杀死细菌。