Environmental Regulation of Staphylococcus epidermidis PIA Synthesis

表皮葡萄球菌PIA合成的环境调控

• 批准号: 7025240
• 负责人: GREG Alan SOMERVILLE
• 金额: $ 18.35万
• 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 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7025240
• 关键词: Staphylococcus; aconitate hydratase; adhesin; bacterial genetics; environmental stressor; enzyme activity; ethanol; gene environment interaction; gene expression; intracellular; iron; isocitrate dehydrogenase; microorganism culture; mutant; nutrition related tag; oxidative stress; polysaccharides; protein biosynthesis; sodium chloride; tricarboxylate

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(申请人提供)：在美国，表皮葡萄球菌每年导致约250,000例医院获得性感染，使其成为医院感染的主要原因。虽然这种机会性病原体产生的疾病的类型和严重程度各不相同，但其最常见的感染表现与留置医疗器械(如导管)有关。导管相关性感染通常涉及细菌生物膜的形成，这一过程需要产生多糖胞间粘附素(PIA)。PIA是一种？-1，6-连接的多糖，与葡萄球菌细胞表面有很强的联系，并介导细胞与细胞之间的黏附。在氧气限制、营养充足或铁限制条件下的生长过程中，PIA的合成增加。重要的是，这些相同的环境条件改变了细菌的新陈代谢状态，从而创造了一种将细胞外环境变化传递到细胞内环境的有效手段。长期目标是了解葡萄球菌如何调节毒力因子的合成，以响应环境刺激。这项应用的目的是确定细胞外环境因素如何改变细胞内的代谢状态，从而影响表皮葡萄球菌PIA合成的变化。这一应用的中心假设是，调节PIA合成的环境因素是通过抑制共同的代谢途径来实现的，特别是三羧酸(TCA)循环。这一假说的起源是观察到影响PIA生产的环境因素也影响TCA循环功能。对这一假设的有力支持是基于观察到表皮葡萄球菌与低浓度的TCA循环抑制剂孵育显著增加了PIA的产量。中心假说预测，诱导TCA循环活动将减少或消除PIA的产生。因此，阻止关键的TCA循环代谢物或氨基酸的运输将需要一个活跃的TCA循环才能使细菌生存，从而限制PIA的合成并降低表皮葡萄球菌形成生物膜的能力。该提案中包含的研究将对确定哪些膜转运蛋白作为疫苗开发的目标产生催化作用。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葡萄球菌生物膜的成熟，从而增加成功治疗感染的可能性。 许多细菌感染对医生来说很难治疗，因为细菌可以在被称为生物膜的致密簇中生长。为了让细菌形成生物膜，它们必须产生一种复杂的糖来将生物膜结合在一起。这项提案中包含的工作是朝着抑制这种复杂糖的形成、防止细菌生物膜的形成以及为医生提供治疗患者的方法迈出的第一步。