Homeostatic control of bacterial growth and cell division

项目摘要 细胞大小控制对生命的所有领域都至关重要，细胞大小的变化是一个重要的指标 影响细胞生长和细胞周期进程之间平衡的扰动。使用像元大小作为 镜头，我们的工作试图开发一个清晰的，集成的，系统水平的自我平衡调节电路的图像 在细菌中协调营养供应与细胞生长和细胞周期进程。在单细胞中 生物体，这些回路确保有限资源的有效分配，最大限度地增加增殖潜力， 并保持生存能力，以应对不断变化的环境条件。这些电路中的缺陷可能是 灾难性的，干扰重要的应激反应机制，严重损害生长和显著 降低了生存能力。不断积累的数据支持全球生物合成能力监管机构的核心作用 分子鸟苷四磷酸(PpGpp)，在调节电路中协调营养有效性与 细菌生理学的不同方面。目前的项目侧重于以下三个方面 PpGpp在其中发挥作用的动态平衡调节网络：1)调节平衡的机制 在细胞侧壁生长和隔壁合成之间，2)信号转导途径协调 与脂肪合成有关的合成代谢的细胞质方面，以确保细胞质体积不 克服质膜能力，以及3)负责细胞分裂的调节电路 资源，以最大限度地生存，以应对营养限制。 抗生素耐药病原体的日益流行提供了额外和强大的 了解细菌如何适应不断变化的环境条件以最大限度地促进生长和 传播。我们最近确定，商业抗菌剂三氯生的预处理增加了 通过ppGpp依赖的机制，抗生素耐受性高达10,000倍。利用这一发现，我们正在 使用遗传策略识别细菌生理中依赖ppGpp的变化，使细胞能够 在通常致命浓度的抗生素中存活。这项工作将增进我们对具体情况的理解 抗生素耐受性的生理适应，并有助于识别 可以绕过它们。 我们在所有这些努力中都得到了我们的多学科方法的帮助，这种方法采用了各种不同的 技术和不同的模型系统，以及密切的同事和 我们与之自由交流试剂和思想的合作者。这些优势使我们能够 回答与生物体相关的生理学和动态平衡控制中以前棘手的问题 在生命之树上。

Project Summary Cell size control is critical to all domains of life and changes in cell size are an important indicator of perturbations that impact the balance between cell growth and cell cycle progression. Using cell size as a lens, our work seeks to develop a clear, integrated, systems-level picture of the homeostatic regulatory circuits coordinating nutrient availability with cell growth and cell cycle progression in bacteria. In single celled organisms, these circuits ensure the efficient partitioning of limited resources, maximize proliferative potential, and preserve viability in response to changing environmental conditions. Defects in these circuits can be catastrophic, interfering with vital stress response mechanisms, severely impairing growth and dramatically reducing viability. Accruing data support a central role for a global regulator of biosynthetic capacity, the small molecule guanosine tetraphosphate (ppGpp), in the regulatory circuits coordinating nutrient availability with divergent aspects of bacterial physiology. Current projects focus on three aspects of these essential homeostatic regulatory networks in which ppGpp plays a role: 1) the mechanisms governing the balance between lateral cell wall growth and septal wall synthesis, 2) the signal transduction pathways coordinating cytoplasmic aspects of anabolic metabolism with lipid synthesis to ensure that cytoplasmic volume does not overcome plasma membrane capacity, and 3) the regulatory circuits responsible for partitioning cellular resources to maximize viability in response to nutrient limitation. The increasing prevalence of antibiotic resistant pathogens provides an additional and powerful motivation to understand how bacteria adapt to changing environmental conditions to maximize growth and propagation. We recently determined that pretreatment with the commercial antimicrobial triclosan increases antibiotic tolerance up to 10,000-fold, through a ppGpp-dependent mechanism. Leveraging this finding, we are employing genetic strategies to identify ppGpp-dependent changes in bacterial physiology that allow cells to survive in normally lethal concentrations of antibiotics. This work will enhance our understanding of the specific physiological adaptations underlying antibiotic tolerance and facilitate the identification of antimicrobials that can circumvent them. We are aided in all these endeavors by our multidisciplinary approach that employs a diverse array of techniques and divergent model systems, as well as an extensive network of close colleagues and collaborators with whom we enjoy a free exchange of reagents and ideas. These advantages allow us to answer previously intractable questions in physiology and homeostatic control that are relevant to organisms throughout the tree of life.