Connecting social interactions to natural product biosynthesis in actinomycete bacteria

项目摘要/摘要 长期以来，细菌的天然产物一直是抗击细菌的第一线防线 感染，还被广泛用作抗真菌、驱虫药、抗癌药物和 免疫抑制药。一组细菌，放线菌，历史上一直是 临床上有用的天然产品。最近的研究表明，天然产物的生物合成通常会导致 来自单个放线菌菌落中细胞之间相互作用形式的微生物通信，或 通过与不同物种的微生物相互作用。总而言之，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由社会驱动的。这项研究的目标是了解内部和外部环境如何 种内相互作用在分子水平上激活了天然产物的生物合成。我们的第一个研究目标 寻求对模式放线菌天蓝色链霉菌如何激活表达的机械理解 在其他放线菌存在的情况下，天然产物生物合成的基因。我们发现这个 激活需要一种在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 寻求对天蓝色链霉菌在细胞环境中天然产物生物合成的系统水平的理解 命运决定。从这一目标产生的知识有朝一日可能被用来操纵细胞的命运 在放线菌培养中推动天然产品的发现和生产。这些目标是并行运行的 随着我们努力建立一个研究微生物种间相互作用的微流控设备，这是前所未有的 速度、吞吐量和专一性。该设备将有多个与我们的前两个目标相关的应用 以及更远的地方。这项研究将阐明天然产品生物合成的社会方面，从长远来看， 为利用微生物社会线索和基因调控提供基础，以最大限度地利用未来的自然 产品发现的努力。 好了！

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. !