Chemical biology of bacterial symbionts

细菌共生体的化学生物学

• 批准号: 8503293
• 负责人: Jon Clardy
• 金额: $ 40.95万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-09 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8503293
• 关键词: Actinobacteria class; Address; Amoeba genus; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antifungal Agents; Antineoplastic Agents; Bacteria; Behavioral Assay; Biological; Biological Assay; Biological Metamorphosis; Biological Models; Biological Process; Biology; Burkholderia; Chemicals; Chemistry; Communicable Diseases; Communication; Communities; Complex; Development; Developmental Process; Dictyostelium discoideum; Eukaryota; Evolution; Face; Flavobacteria; Flavobacterium genus; Fruit; Future; Genetic; Health; Human; Human Development; Human Microbiome; Intercept; Laboratories; Larva; Life; Lipids; Malignant Neoplasms; Marines; Medicine; Membrane; Metabolic; Metabolism; Methods; Modeling; Molecular Evolution; Nematoda; Nutritional; Organism; Pathway interactions; Pharmaceutical Preparations; Play; Polyps; Production; Property; Pseudomonas; Recording of previous events; Regulation; Relative (related person); Reproduction spores; Research; Research Personnel; Resolution; Resources; Role; Signal Transduction; Soil; Solubility; Source; Staging; Swimming; Symbiosis; System; Therapeutic Agents; Vesicle; Virulence; animal model development; antimicrobial drug; aqueous; base; improved; insight; interest; life history; member; metabolomics; novel therapeutics; pathogen; peptide synthase; polyketide synthase; prototype; public health relevance; screening; small molecule; social; tool

DESCRIPTION (provided by applicant): This project addresses a key issue for both biology and medicine: the discovery of small molecules that can serve as the basis for regulating biological processes and/or developing therapeutic agents. Bacteria that live in close association with other organisms, symbiotic bacteria, produce small molecules to regulate the relations with their hosts and other community members, and researchers are just now beginning to appreciate the pervasiveness of these interactions and the legion of biologically active small molecules needed to maintain them. This proposal describes three different approaches to access these small molecules; two focus on specific symbioses, while the third focuses on a general strategy to intercept bacterial messages. 1) The first aim focuses on symbiotic bacteria that are expected to produce antibacterial, antifungal, and nematocidal compounds. Bacteria from several genera - Pseudomonas, Burkholderia, and Flavobacteria among others - are used by some social amoebas (Dictyostelium discoideum) to defend territory, deter predators, and provide a selective advantage over close relatives lacking bacterial symbionts. This aim will find new sources for antimicrobial agents and reveal the genetic basis for virulence and antibiotic resistance in relatives of human pathogens. 2) The second aim focuses on symbiotic bacteria that provide a developmental signal for a model eukaryote. While the biomedical community has long appreciated the ability of certain bacteria to make the defensive small molecules that led to important antibiotic and anticancer agents, the recognition that bacteria also make small molecules that regulate animal development, metabolism and evolution is very recent. Hydroids with their complex multistage life history are an important model for animal development. This aim will define the small molecule signal(s) that turns a free-swimming larva into a sessile hydroid. This project will provide important insights into the origins of the lipid signals that control much of human development. 3) The third specific aim focuses on a common strategy bacteria use to send small molecule messages to their neighbors: tiny vesicles that bud off from bacterial outer membranes called outer membrane vesicles (OMVs). This aim will develop a generally applicable approach to systematically explore the metabolomics of these OMVs in order to quickly distinguish information carrying small molecules from the much less significant metabolic flotsam and jetsam found in bacterial communities.

描述（由申请人提供）：该项目解决了生物学和医学的一个关键问题：发现可以作为调节生物过程和/或开发治疗剂的基础的小分子。与其他生物体密切相关的细菌，即共生细菌，产生小分子来调节与宿主和其他群落成员的关系，研究人员现在才开始认识到这些相互作用的普遍性以及所需的大量生物活性小分子来维护它们。该提案描述了获取这些小分子的三种不同方法；两个关注特定的共生体，而第三个则关注拦截细菌信息的一般策略。 1）第一个目标集中于预期产生抗菌、抗真菌和杀线虫化合物的共生细菌。一些社会性阿米巴原虫（盘基网柄菌）利用来自多个属的细菌（假单胞菌属、伯克霍尔德氏菌属和黄杆菌属等）来保卫领地、威慑捕食者，并提供相对于缺乏细菌共生体的近亲的选择性优势。这一目标将找到抗菌药物的新来源，并揭示人类病原体亲属的毒力和抗生素耐药性的遗传基础。 2）第二个目标侧重于为模型真核生物提供发育信号的共生细菌。虽然生物医学界长期以来一直认识到某些细菌能够产生防御性小分子，从而产生重要的抗生素和抗癌剂，但最近才认识到细菌也能产生调节动物发育、新陈代谢和进化的小分子。水螅具有复杂的多阶段生活史，是动物发育的重要模型。这一目标将定义将自由游动的幼虫转变为固着的水螅的小分子信号。该项目将为控制人类发育的脂质信号的起源提供重要的见解。 3）第三个具体目标侧重于细菌用来向邻居发送小分子信息的常见策略：从细菌外膜上萌芽的微小囊泡，称为外膜囊泡（OMV）。这一目标将开发一种普遍适用的方法来系统地探索这些 OMV 的代谢组学，以便快速区分携带小分子的信息与细菌群落中发现的不太重要的代谢废物和废弃物。