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: 9978837
• 负责人: Matthew F Traxler
• 金额: $ 35.57万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978837
• 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. !

项目摘要/摘要 长期以来，来自细菌的天然产品一直是与细菌斗争的一线防御 感染，还发现广泛用作抗真菌剂，驱虫药，抗癌药和 免疫服。一组细菌（放线菌）历史上一直是最深层的来源 临床上使用的天然产品。最近的工作表明，天然产物生物合成通常会导致 从单个放线菌的菌落中的细胞之间相互作用的微生物通信，或 通过与不同物种的微生物相互作用。这些观察结果共同凸显了这样的观念 自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与 种类的相互作用在分子水平上激活天然产物生物合成。我们的第一个研究目标 寻求对模型放线菌的机械理解，如何激活表达 在存在其他放线菌的存在下，天然产物生物合成的基因。我们发现这个 激活需要在放线菌中发现的异常和不良的信号转导机制 这与依赖G蛋白激活的真核系统相似。我们的第二个研究目标 在细胞的背景下，寻求对S. coelicolor中天然产物生物合成的系统级别的理解 命运决定。从这个目标产生的知识可能被用来有一天操纵细胞命运 在放线菌培养物中，以推动天然产品的发现和生产。这些目标并行运行 我们努力建立一个微流体设备，用于研究与前所未有的微生物间隔相互作用 速度，吞吐量和特异性。该设备将具有与我们的前两个目标有关的多个应用程序 及以后。这项研究将阐明自然产品生物合成的社会方面，从长远来看 为利用微生物社会提示和遗传调节提供基础，以最大程度地提高未来的自然 产品发现工作。 呢