Environmental Regulation of Staphylococcus epidermidis PIA Synthesis

表皮葡萄球菌PIA合成的环境调控

• 批准号: 7229909
• 负责人: GREG Alan SOMERVILLE
• 金额: $ 17.82万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229909
• 关键词: Acids; Aconitate Hydratase; Address; Affect; Amino Acids; Appendix; Bacteria; Bacterial Infections; Catheters; Cell Adhesion; Cell surface; Cells; Citric Acid Cycle; Coenzyme A; Complex; Condition; Cues; Data; Development; Environment; Environmental Risk Factor; Enzymes; Ethanol; Genes; Genus staphylococcus; Goals; Growth; Heating; Infection; Iron; Isocitrate Dehydrogenase; Lead; Link; Measures; Mediating; Medical Device; Membrane Transport Proteins; Metabolic; Metabolic Pathway; Microbial Biofilms; NADH; Nosocomial Infections; Nutrient; Nutritional; Oxaloacetates; Oxidation-Reduction; Oxygen; Patients; Physicians; Polysaccharides; Process; Production; Purpose; Regulation; Research; Severity of illness; Sodium Chloride; Staphylococcus epidermidis; Stimulus; Stress; Testing; Tricarboxylic Acids; Vaccines; Virulence Factors; Work; attenuation; base; biological adaptation to stress; environmental change; extracellular; inhibitor/antagonist; mutant; oxaloacetate; pathogen; polysaccharide intercellular adhesin; prevent; response; sugar; vaccine development

DESCRIPTION (provided by applicant): Staphylococcus epidermidis causes about 250,000 hospital-acquired infections per year in the U.S.A., making it the leading cause of nosocomial infections. Although the type and severity of diseases produced by this opportunistic pathogen varies, its most common infectious manifestation is associated with indwelling medical devices (e.g., catheters). Catheter associated infections usually involve the formation of a bacterial biofilm, a process requiring the production of polysaccharide intercellular adhesin (PIA). PIA is a ?-1, 6-linked polysaccharide that is strongly associated with the staphylococcal cell surface and mediates cell-to-cell adhesion. Synthesis of PIA increases during growth in either oxygen limiting, nutrient replete, or iron-limiting conditions. Importantly, these same environmental conditions alter the metabolic status of the bacteria, thus, creating an effective means to convey extracellular environmental changes to the intracellular environment. The long-term goal is to understand how staphylococci regulate virulence factor synthesis in response to environmental stimuli. The objective of this application is to determine how extracellular environmental factors alter the intracellular metabolic status to affect changes in S. epidermidis PIA synthesis. The central hypothesis of this application is that the environmental factors regulating PIA synthesis do so through the inhibition of a common metabolic pathway, specifically, the tricarboxylic acid (TCA) cycle. The genesis of this hypothesis was the observation that the environmental factors influencing PIA production also affect TCA cycle function. Strong support for this hypothesis is based on the observation that incubation of S. epidermidis with low concentrations of a TCA cycle inhibitor dramatically increases PIA production. The central hypothesis predicts that inducing TCA cycle activity will reduce or eliminate PIA production. Therefore, blocking the transport of a key TCA cycle metabolite or amino acid will require an active TCA cycle for bacterial survival, limiting PIA synthesis and reducing the ability S. epidermidis to form a biofilm. The research contained within this proposal will have a catalytic impact in determining which membrane transporters to target for vaccine development. It is anticipated that vaccines directed against membrane transporters of key TCA cycle molecules, or amino acids, will prevent the maturation of a S. epidermidis biofilm, thus, enhancing the likelihood of successfully treating the infection. [Lay summary] Many bacterial infections are difficult for physicians treat because the bacteria can grow in dense clusters known as biofilms. In order for bacteria to form a biofilm, they must produce a complex sugar to hold the biofilm together. The work contained in this proposal is a first step toward inhibiting the formation of this complex sugar, preventing the formation of a bacterial biofilm, and providing physicians a way to treat patients.

描述（由申请人提供）：表皮葡萄球菌每年在美国引起约25万医院获得感染，使其成为医院感染的主要原因。尽管该机会病原体产生的疾病的类型和严重程度各不相同，但其最常见的感染性表现与留置医疗设备（例如导管）有关。导管相关的感染通常涉及形成细菌生物膜，这是需要产生多糖细胞间粘附素（PIA）的过程。 PIA是一个与葡萄球菌细胞表面密切相关并介导细胞对细胞粘附密切相关的6-1连接多糖。在氧气限制，养分或铁限制条件下，PIA的合成在生长过程中增加。重要的是，这些相同的环境条件改变了细菌的代谢状况，因此创造了一种有效的手段，将细胞外环境变化传达给细胞内环境。长期的目标是了解葡萄球菌如何调节对环境刺激的响应毒力因子的合成。该应用的目的是确定细胞外环境因素如何改变细胞内代谢状态以影响表皮链球菌PIA合成的变化。该应用的中心假设是，调节PIA合成的环境因素是通过抑制常见代谢途径的抑制，特别是三羧酸（TCA）循环。该假设的起源是观察到影响PIA产生的环境因素也会影响TCA循环功能。对这一假设的强烈支持是基于这样的观察结果，即表皮链球菌与低浓度的TCA循环抑制剂的孵育大大增加了PIA的产生。中心假设预测，诱导TCA循环活性将减少或消除PIA的产生。因此，阻断关键TCA循环代谢产物或氨基酸的转运将需要活跃的TCA循环以进行细菌存活，从而限制PIA合成并降低表皮链球菌形成生物膜的能力。该提案中包含的研究将在确定哪种膜转运蛋白靶向疫苗开发时产生催化影响。预计针对关键TCA循环分子或氨基酸的膜转运蛋白的疫苗将防止表皮链球菌生物膜的成熟，从而增强了成功治疗感染的可能性。 [摘要]医师治疗的许多细菌感染很难，因为细菌可以在被称为生物膜的密集簇中生长。为了使细菌形成生物膜，它们必须产生复杂的糖以将生物膜固定在一起。本提案中包含的工作是抑制这种复杂糖的形成，防止细菌生物膜的形成，并为医生提供治疗患者的方法的第一步。