Connecting specialized metabolism to social cues in actinomycete bacteria

项目摘要/摘要 来自细菌的天然产品仍然是抗击 细菌感染，还被广泛用作抗真菌、驱虫剂、抗癌药物 药物和免疫抑制剂。一组细菌，放线菌，在历史上一直是 临床上有用的天然产品的最深层来源。在过去的十年里，有大量的报告 已经证明，天然产物的生物合成通常发生在放线菌的背景下 互动。这些包括不同物种的微生物之间的相互作用，以及细胞与细胞之间的相互作用 单个放线菌群体内的协调作用。总而言之，这些发现巩固了 认为在这些细菌中诱导天然产物生物合成是由社会驱动的。尽管 这种社会方面的重要性，这些相互作用如何在分子水平上展开，以及 如何最好地利用相互作用来发现天然产品仍然是悬而未决的问题。 这项研究的目标是了解物种间和物种内的相互作用是如何激活的 天然产物在分子和系统水平上的生物合成，并建立框架 将这些洞察力转化为天然产品发现。首先，这项工作将研究如何 模式放线菌天蓝色链霉菌激活抗生素基因表达 在其他放线菌存在的情况下产生。此激活需要一个不同寻常的 在具有相似之处的放线菌中发现的信号转导机制知之甚少 依赖于G蛋白激活的真核系统。第二，这项工作寻求一个系统-- 天蓝色链霉菌内空间协调抗生素生产的水平理解 殖民地。从这一目标产生的知识有朝一日可能被用来操纵 放线菌培养中的细胞命运推动天然产物的发现和生产。第三, 这项工作利用放线菌的相互作用来发现新的天然产品。这 研究是将我们对放线菌相互作用的知识应用到 实践，重点是发现具有不寻常作用机制的化合物。在……里面 作为整体，这项工作将阐明天然产品生物合成的社会驱动因素，并在 从长远来看，为利用微生物社会线索和基因调控提供基础 最大限度地提高未来天然产品的发现力度。

PROJECT SUMMARY/ABSTRACT Natural products from bacteria continue to be 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. Over the last decade, numerous reports have demonstrated that natural product biosynthesis often occurs in the context of actinomycete interactions. These include interactions between microbes of different species, and cell-cell coordination within colonies of single actinomycetes. Together, these findings have solidified the idea that induction of natural product biosynthesis is socially driven in these bacteria. Despite the importance of this social aspect, how these interactions unfold at the molecular level and how interactions may best be harnessed for natural products discovery remain open questions. The goals of this study are to understand how inter- and intra- species interactions activate natural product biosynthesis at the molecular and systems levels, and to build framework for translating these insights into natural product discovery. First, this work will examine how the model actinomycete Streptomyces coelicolor activates expression of genes for antibiotic production in the presence of other actinomycetes. 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. Second, this work seeks a systems- level understanding of spatially coordinated antibiotic production within individual S. coelicolor colonies. Knowledge generated from this objective may be employed to someday manipulate cell fates within actinomycete cultures to drive natural products discovery and production. Third, this work leverages actinomycete interactions for the discovery of novel natural products. This research serves as a testbed for putting our knowledge of actinomycete interactions into practice, with an emphasis on discovery of compounds with unusual mechanisms of action. In its entirety, this work will illuminate the social drivers 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.