Metabolism of Pseudomonas aeruginosa under conditions of persistent infection of the cystic fibrosis lung

囊性纤维化肺持续感染条件下铜绿假单胞菌的代谢

• 批准号: 71800214
• 负责人: Privatdozent Dr. Max Schobert
• 金额: --
• 依托单位: Institut für Mikrobiologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/71800214?language=en
• 关键词: Metabolism; Pseudomonas; aeruginosa; under; conditions

Pseudomonas aeruginosa causes persistent lung infections of patients suffering from the genetic disorder cystic fibrosis (CF). It is the dominant bacterium in the sputum of chronically infected CF lungs and often associated with poor prognosis of the patients. Much is known about P. aeruginosa virulence factors and its ability to grow as biofilms during infection. However, the metabolic basis for success of P. aeruginosa in colonization, adaptation and establishing a persistent infection is only partly understood. One reason for this lack of knowledge is that CF-sputum as well as growth conditions in the CF-sputum are difficult to mimic. Consequently, the physiology and the corresponding metabolism of P. aeruginosa under persistent infection conditions are currently unknown, however, of high relevance for the success of this pathogen. Recently, we started the investigation of the P. aeruginosa transcriptome, proteome and metabolome using an artificial sputum medium. We determined metabolic profiles of P. aeruginosa, determined the metabolic pathways in operation during anaerobic growth. In this application we aim to complement our current data with equivalent information for P. aeruginosa grown on CF patient sputum. We will identify the carbon sources crucial for successful growth in CF sputum under microaerobic and anaerobic conditions. We will test how different carbon sources change the physiology, virulence and antibiotic tolerance of P. aeruginosa. A model of the metabolic and regulatory network will be deduced, tested and further developed into a systems biology approach. Furthermore, we will compare the metabolism of P. aeruginosa laboratory strains to clinical isolates adapted to the CF-lung habitat. Results of these studies will shed light on the metabolic strategies employed by P. aeruginosa for the adaptation to conditions in the CF lung. We hope to understand if typical CF mutant phenotypes are caused by this metabolic adaptation process. Clearly, this combined experimental and partly modeled approach will provide a novel rationale to develop alternative strategies and discover new targets for antibiotics to treat P. aeruginosa infections.

铜绿假单胞菌引起患有遗传性疾病囊性纤维化（CF）的患者的持续性肺部感染。它是慢性感染CF肺的痰中的优势细菌，并且通常与患者的不良预后相关。关于铜绿假单胞菌的毒力因子及其在感染期间作为生物膜生长的能力已经知道很多。然而，铜绿假单胞菌成功定植、适应和建立持续感染的代谢基础仅部分了解。这种知识缺乏的一个原因是CF-痰液以及CF-痰液中的生长条件难以模拟。因此，铜绿假单胞菌在持续感染条件下的生理学和相应的代谢目前尚不清楚，然而，与该病原体的成功高度相关。最近，我们开始使用人工痰液培养基研究铜绿假单胞菌的转录组、蛋白质组和代谢组。测定了铜绿假单胞菌的代谢谱，确定了厌氧生长过程中的代谢途径。在本申请中，我们的目标是用CF患者痰液上生长的铜绿假单胞菌的等效信息补充我们目前的数据。我们将确定在微氧和厌氧条件下CF痰液成功生长的关键碳源。我们将测试不同的碳源如何改变铜绿假单胞菌的生理、毒力和抗生素耐受性。代谢和调节网络的模型将推导，测试和进一步发展成一个系统生物学方法。此外，我们将比较铜绿假单胞菌实验室菌株与适应CF-肺生境的临床分离株的代谢。这些研究的结果将揭示铜绿假单胞菌为适应CF肺条件而采用的代谢策略。我们希望了解典型的CF突变表型是否由这种代谢适应过程引起。显然，这种实验和部分建模相结合的方法将为开发替代策略和发现抗生素治疗铜绿假单胞菌感染的新靶点提供新的理论基础。