Molecular mechanism of metabolic adaptation by Staphylococcus aureus

项目摘要 金黄色葡萄球菌（Staphylococcus aureus）是一种多功能的病原体，可以在哺乳动物的皮肤和粘膜上定植 不会引起症状，但它会突然产生危及生命的感染。的机制 这种转变的发生是未知的。金黄色葡萄球菌占30万例住院病例和1.1万例 每年死亡，导致美国的直接医疗费用超过45亿美元。成功 S.金黄色葡萄球菌可能是由于其适应不同代谢环境的能力， 特定宿主代谢环境的差异可能导致这些细菌从 从非致病状态到高致病状态。毒力因子表达的调控是 重要的是S。金黄色葡萄球菌的存活、生长和致病性。S.金黄色 是葡萄球菌外毒素（细胞毒素和肠毒素），通过引起溶解来解除宿主免疫系统的武装 白细胞减少或免疫系统细胞异常激活，导致休克。另一个重要的毒力因子 是细菌细胞壁结构的改变，其赋予逃避宿主免疫监视和抗性 抗生素。代谢是营养物质被同化为能量和生物量的一个完整过程。 相当多的证据表明，代谢适应当地养分供应可以大大影响 S.金黄色葡萄球菌通过改变关键毒力因子的表达。然而，人们对 特定碳源（碳水化合物）在致病性中的作用。金黄色葡萄球菌或潜在的 连接代谢和致病性的调节网络。我们的长期目标是确定 S.金黄色葡萄球菌增加毒力和抗生素耐药性。我们 中心假设是特异性毒力因子的表达与特异性毒素的代谢有关。 这一过程是由碳分解代谢物阻遏（CCR）途径调节的。 这将通过追求以下具体目标进行研究：1）确定特定的 碳水化合物对S.金黄色葡萄球菌的致病性和抗生素耐药性，以及2）确定 碳代谢产物阻遏在S.金黄色。我们希望这项研究能帮助我们 特定的碳水化合物驱动的细胞壁的分子结构的变化。的金黄色 减少先天免疫细胞的识别，增加对抗生素的抵抗力。预计这也将 研究将揭示调节代谢适应的关键代谢中间体， 药物开发针对S.金黄色。

PROJECT SUMMARY Staphylococcus aureus is a versatile pathogen that can colonize the skin and mucous membranes of mammals without causing symptoms, but it can suddenly produce a life-threatening infection. The mechanism by which this transition occurs is not known. Staphylococcus aureus accounts for 300,000 hospitalizations and 11,000 deaths annually, resulting in direct heath care costs of more than $4.5 billion in the United States. The successful pathogenicity of S. aureus may be due to its ability to adapt to different metabolic environments, and it is possible that differences in the metabolic environment in a particular host may cause a transition of these bacteria from a non-pathogenic status to a highly pathogenic status. Regulation of the expression of virulence factors is important to S. aureus for survival, growth, and pathogenicity. The most prominent virulence factors of S. aureus are staphylococcal exotoxins (cytotoxins and enterotoxins) that disarm the host immune system by causing lysis of leukocytes or aberrant activation of immune system cells, leading to shock. Another important virulence factor is alteration of bacterial cell wall structures that confers evasion from host immune surveillance and resistance to antibiotics. Metabolism is an integral process by which nutrients are assimilated into energy and biomass. Considerable evidence indicates that metabolic adaptation to local nutrient availability can greatly affect the pathogenicity of S. aureus by altering expression of key virulence factors. However, very little is known about the role of particular carbon sources (carbohydrates) in the pathogenicity of S. aureus or the underlying regulatory networks linking metabolism and pathogenicity. Our long-term goal is to determine the molecular mechanisms by which metabolic adaptation by S. aureus increases virulence and antibiotic resistance. Our central hypothesis is that the expression of specific virulence factors is linked to the metabolism of specific carbohydrates and that this process is regulated by carbon catabolite repression (CCR) pathways. This will be investigated by pursuing the following specific aims: 1) Determine the effect of particular carbohydrates on alteration of S. aureus pathogenicity and antibiotic resistance, and 2) Determine the role of carbon catabolite repression in metabolic adaptation of S. aureus. We expect this study to lead to identification of specific carbohydrate-driven changes in the molecular architecture of the cell wall of S. aureus which decreases recognition by innate immune cells and increases resistance to antibiotic. It is also expected that this study will reveal key metabolic intermediates regulating in metabolic adaptation which may be exploited pharmaceutically to develop novel therapies against S. aureus.