Connecting social interactions to natural product biosynthesis in actinomycete bacteria

将社交互动与放线菌天然产物生物合成联系起来

• 批准号: 10451652
• 负责人: Matthew F Traxler
• 金额: $ 31.92万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451652
• 关键词: Actinobacteria class; Anabolism; Antibiotics; Antifungal Agents; Antineoplastic Agents; Bacteria; Bacterial Infections; Cells; Chemicals; Clinical; Communication; Cues; Devices; Foundations; Future; GTP-Binding Proteins; Gene Expression; Genetic; Goals; Knowledge; Lead; Microbe; Microfluidic Microchips; Modeling; Molecular; Natural Products; Production; Regulation; Research; Resistance; Running; Signal Transduction; Social Interaction; Source; Specificity; Speed; Streptomyces coelicolor; System; Work; anti-cancer; insight; microbial; microorganism interaction; pathogen; protein activation; social

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. !

项目概要/摘要 细菌的天然产物长期以来一直是对抗细菌的前线防御 感染，并且还广泛用作抗真菌药、驱虫药、抗癌药和 免疫抑制剂。放线菌这一类细菌在历史上一直是微生物最深层的来源。 临床上有用的天然产物。最近的工作表明，天然产物生物合成通常会产生 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讯，或 通过与不同物种的微生物相互作用。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。本研究的目的是了解相互之间和 物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 寻求对模型放线菌（天蓝色链霉菌）如何激活表达的机制理解 在其他放线菌存在下天然产物生物合成的基因。我们发现这 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 寻求在细胞背景下对天蓝色链球菌天然产物生物合成的系统级理解 命运的决定。从这个目标产生的知识有朝一日可能被用来操纵细胞的命运 在放线菌培养物中推动天然产品的发现和生产。这些目标是并行进行的 我们努力构建一种微流体装置，以前所未有的方式研究微生物种间相互作用 速度、吞吐量和特异性。该设备将具有与我们的前两个目标相关的多种应用 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， 为利用微生物社会线索和基因调控以最大限度地提高未来的自然环境奠定了基础 产品发现工作。 ！