Chemical Biology of Microbial Interspecies Signaling

描述(申请人提供)：目前使用的许多治疗药物都是由细菌产生的小分子天然产品。虽然它们在临床环境中的使用对医学是一种恩惠，但这些分子为产生生物体所服务的功能还没有被很好地理解。这种知识上的差距可能会阻碍发现新化合物的努力，这些化合物可能会在未来发展成为有效的疗法。最初被认为主要用作 作为相互破坏的媒介，我们现在认识到，许多微生物产品充当微生物感知的信号，以适应它们的环境。这种对天然产物作用的生态学观点导致了我们的中心假说的发展：细菌合成和分泌大量小信号分子，这些小信号分子影响占据同一栖息地的其他微生物的生理。这一普遍假设推动了我们提出的研究。但我们遵循的实验路线也是由发现驱动的；在过去的几年里，我们发现了新的小分子，它们在微生物世界中调节不同物种之间的相互作用。在这个项目的初始阶段，我们验证了主要概念，即研究物种间相互作用的化学生物学可以导致新的小分子天然产物的发现。像以前一样，我们将继续遵循将微生物生态学、生理学和遗传学与酶学、生物信息学和小分子化学相结合的方法。我们现在的目标是通过提高屏幕的规模和化合物表征的吞吐量，将这种多学科方法提升到一个新的水平。具体地说，我们将沿着三个方向开展研究：(I)我们将进行高通量、广谱筛选，以发现调节物种间相互作用的分子。(Ii)我们将研究特定的生态微生物相互作用，以发现调节它们的分子。(Iii)我们会对已完成基因组测序的放线菌菌株进行配对共培养，以进行基因组辅助的化合物发现。在整个分析过程中，我们将使用不同的方法，从转录效应的纳米串分析到高通量液相色谱/质谱学和成像质谱学，以表征相互作用的性质并确定涉及的分子。

DESCRIPTION (provided by applicant): Many therapeutic agents in use today are small molecule natural products produced by bacteria. While their use in clinical settings has been a boon for medicine, the functions that these molecules serve for the producing organisms are not well understood. This gap in knowledge may hinder efforts at discovering new compounds that may be developed into effective therapeutics in the future. Initially thought to serve primarily as agents of mutual destruction, we now recognize that many microbial products serve as signals that microbes sense in order to adapt to their environment. This ecological perspective of the role of natural products led to the development of our central hypothesis: Bacteria synthesize and secrete a large number of small signaling molecules that affect the physiology of other microbes that occupy the same habitat. This general hypothesis drives our proposed research. But the lines of experimentation we follow are also discovery-driven; over the past few years we have discovered new small molecules that mediate diverse interspecies interactions in the microbial world. In the initial phase of this project, we validated the main concept that studying the chemical biology of interspecies interactions can lead to the discovery of new small molecule natural products. As before, we will continue to follow approaches that meld the disciplines of microbial ecology, physiology, and genetics, with enzymology, bioinformatics, and small molecule chemistry. We now aim to take this multidisciplinary approach to the next level by raising the scale of our screens and increasing the throughput of our compound characterization. Specifically, we will pursue research along three directions aims: (i) We will carry out high-throughput, broad spectrum screens to discover molecules mediating interspecies interactions. (ii) We will investigate specific ecological microbial interactions to discover molecules that mediate them. (iii) We will carry out pair-wise co-cultures of actinomycete strains whose genomes have been sequenced to carry out genome assisted compound discovery. Throughout our analyses, we will use diverse methodologies ranging from Nanostring assays of transcriptional effects to high-throughput liquid chromatography/mass spectrometry and imaging mass spectrometry in order to characterize the nature of the interactions and to define the molecules involved.