Chemical biology of bacterial symbionts

描述(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。细菌与其他有机体--共生细菌--密切相关，它们会产生小分子来调节与宿主和其他社区成员的关系，研究人员刚刚开始意识到这种相互作用的普遍性，以及维持这些相互作用所需的大量具有生物活性的小分子。这项提案描述了三种不同的获取这些小分子的方法；两种侧重于特定的共生，而第三种侧重于拦截细菌信息的一般策略。1)第一个目标集中在有望产生抗菌、抗真菌和杀线虫化合物的共生细菌上。来自几个属的细菌--假单胞菌、伯克霍尔德氏菌和黄杆菌等--被一些社会阿米巴(盘基网毛虫)用来保卫领土，威慑捕食者，并提供了比缺乏细菌共生体的近亲更好的选择优势。这一目标将为抗菌剂寻找新的来源，并揭示人类病原体亲属毒力和抗生素耐药性的遗传基础。2)第二个目标集中在为真核生物模型提供发育信号的共生菌。虽然生物医学界长期以来一直赞赏某些细菌制造防御性小分子的能力，这些小分子导致了重要的抗生素和抗癌药物的产生，但人们最近才认识到，细菌也会制造调节动物发育、新陈代谢和进化的小分子。水生动物具有复杂的多阶段生活史，是动物发育的重要模型。这个目标将定义小分子信号(S)，它将自由游泳的幼虫转变为固着的水母。这个项目将为控制人类大部分发育的脂质信号的起源提供重要的见解。3)第三个具体目标集中在细菌用来向邻居发送小分子信息的常见策略上：从细菌外膜中萌发出来的微小小泡，称为外膜小泡(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，以便快速将携带小分子的信息与细菌群落中发现的不太重要的代谢残渣和废渣区分开来。

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.