Arginine and proline metabolism in Staphylococcus aureus

摘要 金黄色葡萄球菌能够在不同的利基环境中黏附并引起感染 人类的主人。这个项目的总体假设是，金黄色葡萄球菌必须微调其中央新陈代谢，以 快速适应给定组织微环境中可用的不同碳源和氮源。 我们实验室以前的工作发现，金黄色葡萄球菌可以从脯氨酸合成精氨酸。 通过谷氨酸高度保守且特征良好的精氨酸生物合成途径。进一步研究 从PPG的项目#4中，他们发现以生物膜为基础的慢性感染以广泛的 髓系来源的抑制细胞(MDSC)渗透和M2巨噬细胞极化；两种细胞群都利用 细胞外精氨酸作为精氨酸酶的底物，将精氨酸的代谢重定向为鸟氨酸和 形成多胺、脯氨酸和随后的胶原蛋白的合成。基于这些数据，我们有 开发了一种模型，通过该模型，细胞外精氨酸在慢性感染中受到限制。因此，具体来说，我们 提出通过尿素循环连接脯氨酸和精氨酸合成的代谢途径对 形成慢性感染。这项申请有以下具体目的：(I)定义先天免疫 小鼠肾脓肿模型的反应(II)研究金黄色葡萄球菌精氨酸生物合成的调节 确定其在小鼠肾脓肿模型中的重要性；(Iii)探讨尿素酶在肾脓肿模型中的功能 金黄色葡萄球菌肾脓肿的建立和成熟加深对葡萄球菌的认识 体内代谢是开发新型抗菌剂所必需的，它针对特定的代谢途径和 扰乱关键的营养获取途径。

Abstract Staphylococcus aureus has the ability to adhere and cause infections in a wide variety of niches within a human host. The overall hypothesis of this project is that S. aureus must fine-tune its central metabolism for rapid adaptation to different carbon and nitrogen sources available within a given tissue microenvironment. Previous work from our laboratory found that Staphylococcus aureus synthesizes arginine from proline instead of the highly conserved and well-characterized arginine biosynthetic pathway via glutamate. Further studies from Project #4 of this PPG have found that chronic biofilm-based infections are typified by an extensive myeloid-derived suppressor cell (MDSC) infiltrate and M2 macrophage polarization; both cell populations utilize extracellular arginine as a substrate for arginase, which redirects the metabolism of arginine to ornithine and the formation of polyamines, proline and subsequent collagen synthesis. Based on these data, we have developed a model whereby extracellular arginine is limited in a chronic infection. Thus, specifically, we propose that the metabolic pathways connecting proline and arginine synthesis via the urea cycle are critical to establishing a chronic infection. This application has the following specific aims: (i) define the innate immune response in the mouse renal abscess model (ii) investigate regulation of arginine biosynthesis in S. aureus and determine its importance in a mouse renal abscess model, (iii) interrogate function of urease in the establishment and maturation of S. aureus renal abscesses. A greater understanding of staphylococcal metabolism in vivo is required to develop novel antibacterial agents that target specific metabolic pathways and disrupt critical nutrient acquisition pathways.