Local and global regulation of bacterial growth

为了影响人类健康，细菌必须通过连续几轮的生长和分裂来繁殖。 此外，细菌细胞必须使其生长适应不断变化的环境条件，包括微生物的变化。 营养物质的可用性或抗生素的存在，以确保生存。在我们提出的工作中，我们侧重于两个方面 与细菌生长和适应有关的问题。首先，我们问细菌细胞如何局部调节 细胞分裂（cytokinesis）？为了解决这个问题，我们将在我们最近的工作基础上 证明保守的多聚GTdFtsZ是细胞壁合成的动态调节剂， 在细胞分裂期间重塑。这个想法代表了将FtsZ定义为主动调节器的范式转变， 而不是被动的支架，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中的参与者和机制。 我们在我们的模式生物新月柄杆菌中鉴定了从FtsZ到细胞壁代谢的途径。 考虑到对新抗生素的迫切需求和细胞壁作为抗菌靶点的有效性， 完全理解细胞壁代谢的机制和调节是一个关键目标。在我们 第二个问题，我们要问细菌如何适应不断变化的养分供应和其他压力？我们 最近描述了称为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是 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， 这表明当营养缺乏时细胞可能下调增殖过程的机制。 我们将使用遗传学、基因组学和生物化学方法的组合来确定 CdnL失活和ppGpp重编程转录以确保细菌在营养期间存活 限制和其他压力。由于CdnL和ppGpp都涉及对多种胁迫的适应， 这项工作将为我们了解压力和抗生素耐药性机制提供信息， 重要的细菌病原体。

To impact human health, bacteria must reproduce through successive rounds of growth and division. Moreover, bacterial cells must adapt their growth to changing environmental conditions, including changes in nutrient availability or the presence of antibiotics, to ensure survival. In our proposed work, we focus on two questions relevant to bacterial growth and adaptation. In the first, we ask how do bacterial cells locally regulate growth during cell division (cytokinesis)? 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 proliferative processes 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.