Mechanisms of (p)ppGpp action in Staphylococcus aureus

(p)ppGpp 在金黄色葡萄球菌中的作用机制

• 批准号: 423246275
• 负责人: Professorin Dr. Christiane Wolz
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie und Hygiene
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/423246275?language=en
• 关键词: Mechanisms; ppGpp; action; Staphylococcus; aureus

The stringent response of bacteria is characterised by the synthesis of the messenger molecule (p)ppGpp, which interferes with many cellular processes, including transcription, replication and translation. However, the phenotypic consequences resulting from (p)ppGpp accumulation vary among species and can be mediated by different underlying mechanisms. Depending on the species, the stringent response is crucial for diverse biological processes, including differentiation, biofilm formation, antibiotic tolerance, production of secondary metabolites or virulence. It is now clear that there are fundamental differences between the stringent response initially characterised in E. coli and the response in Firmicutes. Differences are seen in both the main players involved in synthesis and degradation of the messengers and in the downstream effects of (p)ppGpp. We elucidated major players and mechanisms of the stringent response in Staphylococcus aureus. In S. aureus the stringent response plays important roles in virulence, phagosomal escape and antibiotic tolerance. From our previous work we identified several genes that are immediately activated upon (p)ppGpp synthesis. The molecular mechanisms of gene activation during the stringent response are not well understood, but such gene activation is important for survival under stress conditions probably in a species specific manner. We aim to unravel the molecular mechanisms and functional consequences of (p)ppGpp-dependent gene activation. Furthermore, we will develop (p)ppGpp sensors to assess the role of possibly stochastic (p)ppGpp synthesis in stress tolerance on the single cell level. Recently, major structural insights concerning the (p)ppGpp synthetase activities of Rel, RelQ and RelP from Firmicutes were gained. However, many of the proposed mechanisms are not yet confirmed in vivo in living organisms. We will establish methods to gain insights into the functional consequence of the allosteric regulation of the (p)ppGpp synthetase/hydrolase activities in S. aureus. With this project we will elucidate the underlying molecular mechanisms leading to the specific stringent response phenotype of S. aureus.

细菌的严格反应的特征是信使分子（p）ppGpp的合成，它干扰许多细胞过程，包括转录、复制和翻译。然而，（p）ppGpp积累所导致的表型后果因物种而异，可以通过不同的潜在机制介导。根据物种的不同，严格的反应对于不同的生物过程至关重要，包括分化，生物膜形成，抗生素耐受性，次级代谢产物或毒力的产生。现在清楚的是，在E.大肠杆菌中的反应和厚壁菌门中的反应。在参与信使合成和降解的主要参与者以及（p）ppGpp的下游效应中均观察到差异。我们阐明了金黄色葡萄球菌严格反应的主要参与者和机制。In S.金黄色葡萄球菌的严格反应在毒力、吞噬体逃逸和抗生素耐受中起重要作用。从我们以前的工作中，我们确定了几个基因，立即激活后（p）ppGpp合成。严格的反应过程中的基因激活的分子机制还没有很好地理解，但这种基因激活是重要的生存压力条件下可能在一个物种的具体方式。我们的目标是解开（p）ppGpp依赖的基因激活的分子机制和功能后果。此外，我们将开发（p）ppGpp传感器，以评估可能的随机（p）ppGpp合成在单细胞水平上的胁迫耐受性中的作用。最近，获得了关于厚壁菌门的Rel、RelQ和RelP的（p）ppGpp合成酶活性的主要结构见解。然而，许多提出的机制尚未在活生物体中得到体内证实。我们将建立方法，以获得洞察的功能后果的变构调节的（p）ppGpp合成酶/水解酶活性在S。金黄色。通过本项目，我们将阐明导致S.金黄色。