Chemical Biology of Microbial Interspecies Signaling

描述（由申请人提供）：目前使用的许多治疗剂是由细菌产生的小分子天然产物。虽然它们在临床环境中的使用对医学来说是一个布恩，但这些分子为生产生物体服务的功能还没有得到很好的理解。这种知识上的差距可能会阻碍发现新化合物的努力，这些化合物可能在未来发展成为有效的治疗药物。最初被认为主要是作为 由于微生物是相互破坏的媒介，我们现在认识到，许多微生物产物是微生物为了适应环境而感知的信号。这种对天然产物作用的生态学观点导致了我们核心假设的发展：细菌合成并分泌大量小信号分子，这些分子影响占据相同栖息地的其他微生物的生理学。这个一般假设推动了我们提出的研究。但我们遵循的实验路线也是以发现为导向的;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介导了多种物种间的相互作用。在该项目的初始阶段，我们验证了研究物种间相互作用的化学生物学可以发现新的小分子天然产物的主要概念。和以前一样，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学科融合的方法。我们现在的目标是通过提高筛选的规模和增加化合物表征的通量，将这种多学科方法提升到一个新的水平。具体而言，我们将沿着沿着三个方向进行研究：（i）我们将进行高通量，广谱筛选，以发现介导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，以发现介导它们的分子。(iii)我们将进行基因组测序的放线菌菌株的成对共培养，以进行基因组辅助化合物发现。在整个分析过程中，我们将使用多种方法，从转录效应的Nanostring测定到高通量液相色谱/质谱和成像质谱，以表征相互作用的性质并定义所涉及的分子。

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.