Metabolic remodeling during Bacillus subtilis biofilm development

大多数细菌自然聚集形成复杂的群落，称为生物膜，通过一个复杂的过程，包括分泌一种粘稠的物质，使细胞相互粘附并粘附在表面，从而为群落提供保护，免受恶劣环境、其他细菌和捕食者以及抗生素的侵害。这些生物膜在自然环境中丰富，在许多临床、工业和生态环境中发挥着重要作用。例如，在河流和湖泊中发现的细菌生物膜是食物链的关键组成部分；石油和天然气管道中的生物膜会导致严重的腐蚀问题；与农作物有关的生物膜可能引起疾病，也可能对植物有益；医院的生物膜显著增加了感染传播的风险和感染的持续时间。由于生物膜的普遍存在和对人类活动的重大影响，显然需要更好地了解这些生物膜是如何形成的。该项目将研究生物膜的一个关键但鲜为人知的方面：细胞中最重要的一般反应（称为中枢代谢）在生物膜发育过程中所起的作用。该项目将首次深入研究细菌生物膜形成过程中细胞中的一般反应是如何变化的，并有可能从根本上改变我们对细胞加入生物膜群落时真正发生的事情的理解，以及我们如何能够促进或干扰生物膜的形成。此外，该项目将通过研究生和本科生参与研究活动和培训，以及通过培养对微生物学领域的热情的推广活动，对教育产生重大的更广泛的影响。本项目的主要假设是，中心碳氮代谢的动态重塑是生物膜发育过程中高度协调的生理反应的重要组成部分。利用枯草芽孢杆菌作为模式生物，这项工作将整合最先进的系统级代谢组学和蛋白质组学方法、显微镜和定量计算模型，以产生以下结果：1)对生物膜形成过程中代谢如何重塑的系统级定量理解；2)阐明生物膜形成过程中代谢重塑的驱动调控机制；3)关于生物膜细胞亚群代谢异质性的新见解；4)阐明生物膜发育过程中主要代谢变化的生理相关性。这些结果将显著促进对生物膜调控网络复杂信号系统背后的潜在逻辑和统一原则的理解，并将提供对代谢在生物膜发育中的作用的整体和定量理解。

Most bacteria naturally congregate to form complex communities called biofilms through an elaborate process that involves secretion of a thick, gooey substance that allows cells to stick to each other and to surfaces, thus providing the community with protection against harsh environments, other bacteria and predators, and antibiotics. These biofilms are abundant in natural environments and play an important role in many clinical, industrial, and ecological settings. For example, bacterial biofilms found in rivers and lakes are critical components of food chains; biofilms in oil and gas pipelines can lead to severe corrosion problems; biofilms associated with agricultural crops can either cause disease or be beneficial to plants; and biofilms in hospitals contribute significantly to risk of infection transmission and to the staying power of infections. Due to the ubiquity and significant impacts of biofilms on human activities, there is a clear need to better understand how these biofilms develop. This project will investigate a critical but poorly understood aspect of biofilms: the role that the most important general reactions of the cell (called central metabolism) play during biofilm development. This project will provide the first in depth investigation of how the general reactions in a cell change during bacterial biofilm formation, and has the potential to fundamentally transform our understanding of what really happens to cells when they join a biofilm community and how we might be able to encourage or interfere with biofilm formation. In addition, this project will have significant broader impacts on education through the participation of graduate and undergraduate students in research activities and training, as well as through outreach activities that foster enthusiasm for the field of microbiology.The overarching hypothesis in this project is that dynamic remodeling of central carbon and nitrogen metabolism constitutes an essential component of the highly coordinated physiological response that takes place during biofilm development. Using Bacillus subtilis as a model organism, the work will integrate state-of-the-art systems-level metabolomic and proteomic approaches, microscopy, and quantitative computational modeling, to generate the following outcomes: 1) a systems-level quantitative understanding of how metabolism is remodeled during biofilm formation; 2) elucidation of driving regulatory mechanisms controlling metabolic remodeling during biofilm formation; 3) novel insights regarding metabolic heterogeneity within biofilm cell subpopulations; and 4) elucidation of the physiological relevance of major metabolic alterations during biofilm development. These results will significantly advance the understanding of the underlying logic and unifying principles behind the complex signaling systems of the biofilm regulatory network and will provide a holistic and quantitative understanding of the role of metabolism in biofilm development.