Connecting social interactions to natural product biosynthesis in actinomycete bacteria

项目概要/摘要 细菌天然产物长期以来一直是对抗细菌的前线防御 感染，并且还发现广泛用作抗真菌药、驱虫药、抗癌药和抗肿瘤药。 免疫抑制剂有一类细菌，放线菌，历史上一直是最深层的微生物来源。 临床上有用的天然产物。最近的研究表明，天然产物的生物合成往往导致 来自微生物通讯，其形式为单个放线菌菌落中细胞之间的相互作用，或 通过与不同种类的微生物的相互作用。总之，这些观察结果强调了这样一个观点， 天然产物生物合成的诱导是社会驱动的。这项研究的目的是了解如何在内部和 种内相互作用在分子水平上激活天然产物的生物合成。我们的第一个研究目标 寻求一种模式放线菌天蓝色链霉菌如何激活表达的机制理解， 在其他放线菌存在的情况下进行天然产物生物合成的基因。我们发现该 激活需要放线菌中发现的不寻常且知之甚少的信号转导机制 这与依赖G蛋白激活的真核系统有相似之处。我们的第二个研究目标 寻求系统水平的理解天然产物的生物合成在S。在细胞环境中的腔棘鱼 命运的决定从这一目标产生的知识可能有一天会被用来操纵细胞命运 在放线菌培养中，推动天然产品的发现和生产。这些目标是并行的 随着我们努力建立一个微流体装置，用于研究微生物物种间的相互作用， 速度、通量和特异性。该设备将有多个应用程序与我们的前两个目标 以及更远的地方这项研究将阐明天然产物生物合成的社会方面，从长远来看， 为利用微生物的社会线索和遗传调控提供基础，以最大限度地提高未来的自然 产品发现的努力。 !

PROJECT SUMMARY/ABSTRACT Natural products from bacteria have long been the frontline defense in the struggle against bacterial infections, and have also found wide use as antifungals, anthelminthics, anti-cancer drugs, and immunosupressants. One group of bacteria, the actinomycetes, has historically been the deepest source of clinically-useful natural products. Recent work has demonstrated that natural product biosynthesis often results from microbial communication in the form of interactions between cells in colonies of a single actinomycete, or by interactions with microbes of different species. Together, these observations underscore the idea that induction of natural product biosynthesis is socially-driven. The goal of this study is to understand how inter- and intra- species interactions activate natural product biosynthesis at a molecular level. Our first research objective seeks a mechanistic understanding of how a model actinomycete, Streptomyces coelicolor, activates expression of genes for natural product biosynthesis in the presence of other actinomycetes. We have found that this activation requires an unusual and poorly-understood signal transduction mechanism found in actinomycetes that shares parallels with eukaryotic systems that rely on G protein activation. Our second research objective seeks a systems-level understanding of natural product biosynthesis in S. coelicolor within the context of cell fate decisions. Knowledge generated from this objective may be employed to someday manipulate cell fates within actinomycete cultures to drive natural products discovery and production. These objectives run in parallel with our efforts to build a microfluidic device for studying microbial interspecies interactions with unprecedented speed, throughput, and specificity. This device will have multiple applications related to our first two objectives and beyond. This research will illuminate the social aspect of natural product biosynthesis, and in the long term, provide a foundation for harnessing microbial social cues and genetic regulation to maximize future natural products discovery efforts. !