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）：在美国，表皮葡萄球菌每年导致约25万例医院获得性感染，是医院感染的主要原因。虽然这种机会致病菌引起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（如导尿管）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细胞间粘附素（PIA）。PIA是一个？与葡萄球菌细胞表面密切相关并介导细胞间粘附的- 1,6 -linked多糖。在限氧、营养充足或限铁条件下，PIA的合成都会增加。重要的是，这些相同的环境条件改变了细菌的代谢状态，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合成以响应环境刺激。本应用程序的目的是确定细胞外环境因素如何改变细胞内代谢状态，从而影响表皮葡萄球菌PIA合成的变化。本应用的中心假设是，调节PIA合成的环境因素是通过抑制一个共同的代谢途径，特别是三羧酸（TCA）循环来实现的。这一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循环来维持细菌的生存，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。本提案中包含的研究将对确定疫苗开发的靶膜转运蛋白具有催化作用。预计针对关键TCA循环分子或氨基酸的膜转运体的疫苗将阻止表皮葡萄球菌生物膜的成熟，从而提高成功治疗感染的可能性。