Molecular mechanism of metabolic adaptation by Staphylococcus aureus

项目总结 金黄色葡萄球菌是一种多种病原体，可定植于哺乳动物的皮肤和粘膜。 没有引起症状，但它可以突然产生一种危及生命的感染。这一机制通过它 这种转变的发生尚不清楚。金黄色葡萄球菌占30万人住院和11,000人 每年的死亡人数，导致美国直接医疗费用超过45亿美元。成功者 金黄色葡萄球菌的致病性可能是由于其适应不同代谢环境的能力，这是可能的 特定宿主的代谢环境的差异可能会导致这些细菌从 从非致病状态到高致病状态。毒力因子表达的调控是 对金黄色葡萄球菌的生存、生长和致病性很重要。金黄色葡萄球菌最显著的毒力因子 金黄色葡萄球菌外毒素(细胞毒素和肠毒素)是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素 是细菌细胞壁结构的改变使其逃避宿主的免疫监视和抵抗 到抗生素。新陈代谢是营养物质被吸收为能量和生物量的完整过程。 大量证据表明，新陈代谢对当地养分供应的适应可以极大地影响 金黄色葡萄球菌通过改变关键毒力因子的表达而致病。然而，人们对此知之甚少。 特定碳源(碳水化合物)在金黄色葡萄球菌致病中的作用或潜在的 将新陈代谢和致病性联系起来的调控网络。我们的长期目标是确定分子 金黄色葡萄球菌代谢适应增加毒力和抗生素耐药性的机制。我们的 中心假设是特定毒力因子的表达与特定毒力因子的新陈代谢有关。 这一过程受碳分解代谢抑制(CCR)途径的调节。 将通过追求以下具体目标来调查这一点：1)确定特定的影响 碳水化合物对金黄色葡萄球菌致病性和耐药性的改变，以及2)决定作用 金黄色葡萄球菌代谢适应中的碳分解代谢抑制。我们希望这项研究将导致识别 由特定的碳水化合物引起的金黄色葡萄球菌细胞壁分子结构的变化 减少先天免疫细胞的识别能力，增加对抗生素的抵抗力。这也是预计的， 研究将揭示在代谢适应中调节的关键代谢中间体，这是可能被开发的 在药物方面开发对抗金黄色葡萄球菌的新疗法。

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.