Chemical biology of bacterial symbionts

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/或开发治疗剂基础的小分子。与其他生物密切相关的细菌，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和维持这些相互作用所需的大量生物活性小分子。该提案描述了三种不同的方法来获取这些小分子；其中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)第一个目标是关注有望产生抗菌、抗真菌和杀线虫化合物的共生细菌。假单胞菌、伯克霍尔德菌和黄杆菌等几种属的细菌被一些群居阿米巴虫（盘状盘齿虫）用来保卫领土、威慑捕食者，并在缺乏细菌共生体的近亲中提供选择优势。这一目标将发现抗菌剂的新来源，并揭示人类病原体近亲的毒力和抗生素耐药性的遗传基础。2)第二个目标侧重于共生细菌，为模式真核生物提供发育信号。虽然生物医学界早就认识到某些细菌具有制造防御性小分子的能力，这种能力导致了重要的抗生素和抗癌剂的产生，但人们最近才认识到细菌也能制造调节动物发育、新陈代谢和进化的小分子。水螅体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，使自由游动的幼虫变成无根的液体。这个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共同策略：从细菌外膜上冒出的小泡，称为外膜泡（OMVs）。该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信息的细菌群落中不太重要的代谢漂浮物和喷气物。

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.