Local and global regulation of bacterial growth

细菌生长的局部和全局调节

• 批准号: 10132354
• 负责人: Erin D Goley
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10132354
• 关键词: Address; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteria; Biochemical; Biochemistry; Caulobacter; Caulobacter crescentus; Cell Wall; Cell division; Cells; Development; Ensure; Genetic; Genetic Transcription; Genomics; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Health; Human; Image; In Vitro; Laboratories; Maps; Metabolism; Nutrient; Pathway interactions; Polymers; Process; Regulation; Reproduction; Research; Role; Signal Pathway; Signal Transduction; Starvation; Stress; Work; bacterial genetics; environmental change; novel; pathogenic bacteria; reconstitution; resistance mechanism; scaffold; transcriptional reprogramming

To impact human health, bacteria must reproduce through successive rounds of growth and cell division. Moreover, bacteria must be able to adapt their growth to changing environmental conditions, including changes in nutrient availability or the presence of antibiotics, to ensure survival. Research in my laboratory focuses on two unanswered questions central to bacterial growth and adaptation. In the first, we ask how do bacterial cells locally regulate growth to achieve cell division? To address this question, we will build on our recent work demonstrating that the conserved, polymerizing GTPase FtsZ is a dynamic regulator of cell wall synthesis and remodeling during cell division. This idea represents a paradigm shift in defining FtsZ as an active regulator, rather than passive scaffold, for cell wall metabolism. We will leverage our expertise in bacterial genetics, imaging, biochemistry, and in vitro reconstitution to map the players and mechanisms in two signaling pathways from FtsZ to cell wall metabolism we identified in our model organism, Caulobacter crescentus. Given the urgent need for new antibiotics and proven efficacy of the cell wall as an antibacterial target, a complete understanding of the mechanisms and regulation of cell wall metabolism is a critical goal. In our second question, we ask how do bacteria adapt to changing nutrient availability and other stresses? We recently described the role of a conserved transcriptional regulator called CdnL in regulating metabolism, specifically in upregulating biosynthetic pathways, in Caulobacter. In addition, we have observed that CdnL is cleared from the cell during nutrient limitation in a manner dependent on the signaling alarmone ppGpp, suggesting a mechanism by which cells may downregulate transcription of proliferative pathways when nutrients are scarce. We will use a combination of genetic, genomic, and biochemical approaches to determine the contributions of CdnL inactivation and ppGpp to reprogramming transcription to ensure bacterial survival during nutrient limitation and other stresses. As both CdnL and ppGpp are implicated in adaptation to a variety of stresses in diverse bacteria, this work will inform our understanding stress and antibiotic resistance mechanisms in important bacterial pathogens.

为了影响人类健康，细菌必须通过连续几轮的生长和细胞分裂来繁殖。 此外，细菌必须能够适应不断变化的环境条件，包括变化 营养物质的可用性或抗生素的存在，以确保生存。我实验室的研究重点是 对于细菌生长和适应来说，两个悬而未决的核心问题。首先，我们问细菌细胞如何 局部调节生长以实现细胞分裂？为了解决这个问题，我们将在最近的工作基础上 证明保守的聚合 GTPase FtsZ 是细胞壁合成的动态调节剂 细胞分裂过程中的重塑。这个想法代表了将 FtsZ 定义为主动监管机构的范式转变， 而不是被动支架，用于细胞壁代谢。我们将利用我们在细菌遗传学方面的专业知识， 成像、生物化学和体外重建，以绘制两种信号传导的参与者和机制 我们在模型生物新月柄杆菌中发现了从 FtsZ 到细胞壁代谢的途径。 鉴于对新抗生素的迫切需求以及细胞壁作为抗菌靶标的功效已得到证实， 完整了解细胞壁代谢的机制和调节是一个关键目标。在我们的 第二个问题，我们问细菌如何适应不断变化的营养供应和其他压力？我们 最近描述了一种名为 CdnL 的保守转录调节因子在调节代谢中的作用， 特别是在柄杆菌中上调生物合成途径。此外，我们观察到 CdnL 在营养限制期间以依赖于信号报警素 ppGpp 的方式从细胞中清除， 表明细胞可能下调增殖途径转录的机制 营养物质匮乏。我们将结合使用遗传、基因组和生化方法来确定 CdnL 失活和 ppGpp 对重编程转录以确保细菌存活的贡献 在营养限制和其他压力期间。由于 CdnL 和 ppGpp 都与适应多种 不同细菌的压力，这项工作将有助于我们了解压力和抗生素耐药性 重要细菌病原体的机制。