Unlocking the biomedical potential of microbial symbionts from complex ecosystems

项目概要/摘要 迫切需要新的治疗方法来治疗需求未得到满足的疾病，如新出现的 感染和免疫性疾病。自然界中产生的特殊代谢产物（天然产物）具有 历史上在药物发现中发挥了关键作用，然而，高比率的重新发现导致了显着的 候选药物的下降。这项拟议研究计划的长期目标是使用一种基于生态学的 探索平台，以调查复杂的生态系统，特别是海洋卵群的微生物群， 存在进化压力，以进化出可用作抗感染剂的专门代谢物， 免疫调节治疗剂。 天然产物在临床上的成功是由于它们的进化历史、它们的结构和 在数百万年的选择性压力下，这些功能演变成了生产的重要角色。 有机体例如，今天临床上使用的许多抗生素都是由陆地生产的。 微生物利用它们来击败竞争对手。海洋卵块的微生物组提供了 有趣的潜在药物候选人的来源，因为它已被假设，进化的压力，导致 防御性代谢物的发展，这些防御性代谢物可以重新用于治疗 人类感染。我们的第一个长期目标是将卵块微生物群建立为一个多样化的宿主， 细菌共生体，然后使用这些共生体构建天然产物级分文库。这个馏分库 已在多种生物测定中筛选，最初的重点是抗感染和免疫调节 分析，和天然产品的组成部分，每一个馏分正在剖析与创新的代谢组学 技术、基于核磁共振的MADByTE和基于质谱的GNPS。活性 成分将被阐明，其生物合成基因簇鉴定，并在体内啮齿动物中进行评价 模型我们的第二个目标是利用分离的微生物产生新代谢物的能力， 已经揭示了在典型的实验室条件下仅产生一部分（< 25%）的代谢物。 使用基于社区的共培养技术和利用收集的卵群的创新技术 将使我们能够复制生态环境中发生的许多化学相互作用， 已知在这些沉默代谢物的调节中起重要作用。 总的来说，我们提出的研究计划将通过建立海洋卵群来广泛影响该领域， 一个新的天然产品的良好来源。研究这些细菌共生体产生的小分子 将导致新的抗感染药物的发现，并有可能重新填充药物管道 针对未得到解决和日益频繁的疾病。

Project summary/abstract New therapeutics are desperately needed for the treatment of diseases with unmet needs, such as emerging infections and immunological diseases. Specialized metabolites (natural products) produced in nature have historically played a critical role in drug discovery, however high rates of rediscovery have resulted in a significant drop in drug candidates. The long-term goal of this proposed research program is to use an ecology-based discovery platform to investigate complex ecosystems, specifically the microbiota of marine egg masses, where evolutionary pressures exist to evolve specialized metabolites that can be leveraged as anti-infective and immunomodulating therapeutics. The success natural products have had in the clinic is due to their evolutionary history, their structures and functions evolved over millions of years of selective pressures to carry out an essential role for the producing organism. For example, many of the antibiotics used in the clinic today are produced by terrestrial microorganisms that use them to vanquish competitors. The microbiomes of marine egg masses provide an intriguing source of potential drug candidates as it has been hypothesized that evolutionary pressure has led to the development of defensive metabolites and these defensive metabolites can be repurposed for the treatment of infections in humans. Our first long term goal is to establish the egg mass microbiota as a host of diverse bacterial symbionts and then using these symbionts to build a natural product fraction library. This fraction library has been screened in a variety of biological assays, with an initial focus on anti-infective and immunomodulating assays, and the natural products components of each fraction are being profiled with innovative metabolomics techniques, nuclear magnetic resonance-based MADByTE and mass spectrometry-based GNPS. Active components will be elucidated, their biosynthetic gene clusters identified, and evaluated in an in vivo rodent model. Our second goal is to leverage the ability of the isolated microbes to produce novel metabolites as studies have revealed that only a fraction (< 25%) of the metabolites are produced under typical laboratory conditions. Using a community-based co-culturing technique and innovative techniques that utilize collected egg masses will allow us to replicate many of the chemical interactions that occur in the ecological environment, which are known play an important role in the regulation of these silent metabolites. Collectively, our proposed research program will broadly impact the field by establishing marine egg masses as a good source of novel natural products. Studying the small molecules produced by these bacterial symbionts will lead to the discovery of novel anti-infective agents and has the potential to repopulate the drug pipeline targeting unmet and increasingly frequent diseases.