B SUBTILIS ECF SIGMA FACTORS: ROLES AND REGULATION

枯草芽孢杆菌 ECF 西格玛因素：作用和监管

• 批准号: 6627176
• 负责人: John D Helmann
• 金额: $ 27.83万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6627176
• 关键词: Bacillus subtilis; DNA directed RNA polymerase; antibiotics; bacterial genetics; bacterial proteins; cell wall; drug resistance; enzyme activity; enzyme mechanism; gene expression; genetic regulatory element; nucleic acid sequence; protein structure function; proteomics; site directed mutagenesis; transcription factor

DESCRIPTION (adapted from the investigator's summary): The widespread emergence of antibiotic resistant bacteria poses a grave threat to our ability to manage and control infectious disease. While tremendous progress has been made in understanding the role of transmissible plasmids and high-level resistance genes in antibiotic resistance, the role and regulation of chromosomally-encoded determinants is less well understood. This project focuses on the genetically well characterized model organism Bacillus subtilis, to investigate the functional genomics of antibiotic resistance and responses. The close evolutionary between B. subtilis and important human pathogens (especially Staphylococcus aureus, Mycobacterium tuberculosis, Enterococcus, and Streptococcus), allows knowledge gained in our system to be directly used in understanding the other. The goal of this project is to understand the role of alternative sigma factors in coordinating the genetic responses triggered by exposure of B. subtilis to antibiotics that target the cell envelope. Recently, the SigX and SigW regulators have been found to activate transcription of a large number of genes affecting the structure and function of cell surface polymers, antibiotic resistance mechanisms, and the production of antimicrobial peptides. Expression of these sigma factors is strongly induced by several clinically important antibiotics, including vancomycin and cephalospirins. To better define these genetic responses, and their roles in protecting the cell against antibiotics, two aims will be pursued. First, promoters controlled by each sigma factor will be identified and the rules that govern promoter selectivity will be explored. The identification of target promoters will reveal the complete set of genes (the regulon) activated by each sigma. The PI will define the overlap the overlap between the various regulons controlled by SigX, SigW and other sigma factors. This aim will include both proteomics and genomics based approaches. Second, the physiological roles of selected taarget genes will also be investigated. For this aim the PI will focus on those operons implicated on defense against antibiotics, modification of the cell envelope, or the production of antimicrobial compounds. In addition, the signaling pathways that control the expression of these regulons will be investigated. Although many different antibiotics can induce each regulon, it is likely that these antibiotics lead to the accumulation of common signaling molecules that are perceived by the anti-sigma factor which then releases the sigma factor. Genetic approaches have been devised to identify components of these signaling pathways. Together, these two aims will provide a unified picture of these two large regulons and their roles in B. subtilis physiology.

描述(改编自调查人员的总结)：广泛的出现 对我们的管理能力构成了严重的威胁 并控制传染病。虽然在以下方面取得了巨大的进展 了解可传递质粒和高水平抗性的作用 抗生素耐药性中的基因、作用及调控 人们对染色体编码的决定因素知之甚少。这个项目 重点关注遗传特性良好的模式生物枯草芽孢杆菌， 目的：研究抗生素耐药和应答的功能基因组学。 枯草杆菌与人类重要病原体的密切进化 (尤其是金黄色葡萄球菌、结核分枝杆菌、肠球菌、 和链球菌)，允许在我们的系统中获得的知识被直接使用 在理解对方方面。 本项目的目标是了解替代西格玛因素的作用。 在协调枯草杆菌暴露于 靶向细胞膜的抗生素。最近，SigX和SigW 已发现调节剂可以激活大量基因的转录 影响细胞表面聚合物结构和功能的抗生素 抗药性机制和抗菌肽的生产。表达式 在这些西格玛因子中，有几个在临床上很重要 抗生素，包括万古霉素和头孢螺菌素。 为了更好地定义这些遗传反应，以及它们在保护 细胞对抗抗生素，将追求两个目标。首先，发起人受到控制 每一个西格玛因素都将被识别出来，并确定管理推动者的规则 将探索选择性。目标发起人的确定将 揭示由每个西格玛激活的一整套基因(调节子)。《少年派》 将定义重叠由控制的各种规则之间的重叠 SigX、SigW等西格玛因素。这一目标将包括蛋白质组学和 基于基因组学的方法。第二，精选目标的生理作用 基因也将被调查。为此，国际和平研究所将把重点放在 操纵子涉及对抗生素的防御，细胞的修饰 信封，或生产抗菌化合物。此外， 控制这些调节子表达的信号通路将是 调查过了。虽然许多不同的抗生素可以诱导每个调节子，但它 很可能是这些抗生素导致了共同信号的积累 被反西格玛因子感知的分子，然后释放 西格玛因素。已经设计出遗传方法来识别 这些信号通路。这两个目标加在一起，将提供一个统一的 这两个大的调节子及其在枯草杆菌生理学中的作用。