Revisiting the bacterial cell wall as a target for new antibiotics

描述（由申请人提供） 翻译后摘要：细菌使用细胞壁来控制许多亚细胞组分在空间和时间的组织。细胞壁在细菌中起着“细胞骨架”的作用，保护细胞免受机械应力的影响。细胞壁上巨大的渗透压（>1个大气压）要求严格控制细胞生长，因为细胞壁上的小缺陷是灾难性的。从分子水平上理解将必需蛋白质定位于细胞壁的组装、性质和机制，将为深入了解这一基本结构的内部工作提供基础。定位于细胞壁并对其进行调节和重塑的蛋白质的鉴定将通过重新启动对这种细胞材料作为药物靶点的兴趣，为抗生素开发的新篇章打开大门。我的实验室将利用我们在化学生物学、生物化学、生物物理学和材料科学与工程方面的经验，采用多学科方法研究细菌细胞壁。我们的重点集中在两个目标：1。我们将开发一种高通量的，基于材料科学的技术，用于测量细菌细胞壁的机械性能。利用这种能力，我们将分析整个基因组范围内收集的大肠杆菌单基因突变体，以确定调节其物理特性的蛋白质。2.我们将开发一套基于材料科学的方法来控制细菌中的细胞壁曲率，并将研究细胞壁的形状如何调节脂质微区的形成，脂质微区反过来又参与细胞质蛋白的细胞内定位。我们将开发针对这些目标中确定的蛋白质的小分子，并将使用它们使用化学生物学方法研究这些分子在体内的功能。这些研究的结果将为细菌细胞的基本过程提供新的线索，并将揭示调节细菌生理学的机制。这些机制和分子将刺激开发有效的抗生素，用于预防和治疗人类感染。 公共卫生相关性：这项研究将确定调节细菌细胞壁结构和组织的新蛋白质和机制。这些结果将导致开发针对病原菌的新型抗生素。

DESCRIPTION (Provided by the applicant) Abstract: Bacteria use the cell wall to control the organization of many sub-cellular components in space and time. The cell wall functions as the 'cytoskeleton' in bacteria and protects cells from mechanical stress. The enormous osmotic pressure across the cell wall (>1 atm) requires that cell growth be tightly regulated, as small defects in the cell wall are catastrophic. A molecular understanding of the assembly, properties, and mechanisms for localizing essential proteins to the cell wall will provide fundamental insight into the inner working of this essential structure. The identification of proteins that are localized to the cell wall and regulate and remodel it will open the door to a new chapter in antibiotic development by rebooting an interest in this cellular material as a drug target. My laboratory will use a multidisciplinary approach to study the bacterial cell wall by drawing on our experience in chemical biology, biochemistry, biophysics, and materials science and engineering. Our focus centers upon two aims: 1. We will develop a high-throughput, materials science-based technique for measuring the mechanical properties of bacterial cell walls. Using this capability we will analyze the entire genome-wide collection of Escherichia coli single gene mutants to identify proteins that modulate its physical properties. 2. We will develop a suite of materials science-based approaches for controlling cell wall curvature in bacteria and will study how the shape of the cell wall regulates the formation of lipid microdomains, which in turn participates in the intracellular localization of cytoplasmic proteins. We will develop small molecules that target the proteins identified in these aims and will use them to study the function of these molecules in vivo using a chemical biological approach. The results of these studies will shed new light on essential processes in bacterial cells and will uncover mechanisms for regulating bacterial physiology. These mechanisms and molecules will stimulate the development of potent classes of antibiotics that have applications in preventing and treating human infections. Public Health Relevance: This research will identify new proteins and mechanisms that regulate the structure and organization of the bacterial cell wall. The results will lead to the development of new classes of antibiotics against pathogenic bacteria.