Unlocking the biomedical potential of microbial symbionts from complex ecosystems

项目摘要/摘要 迫切需要新的疗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。在自然界中产生的特殊代谢物(天然产物)有 从历史上看，药物发现发挥了关键作用，然而，高再发现率导致了显著的 毒品候选人中的一员。这一拟议研究计划的长期目标是使用一种基于生态的 探索平台，研究复杂的生态系统，特别是海洋卵块的微生物区系，其中 进化压力是存在的，需要进化出专门的代谢物，这些代谢物可以被用作抗感染和 免疫调节疗法。 天然产物在临床上取得的成功是由于它们的进化史，它们的结构和 功能在数百万年的选择性压力下进化，以执行生产的基本角色 有机体。例如，今天临床上使用的许多抗生素都是由陆地生物生产的 利用它们来击败竞争对手的微生物。海洋卵块的微生物群提供了一种 潜在候选药物的有趣来源，因为已经假设进化压力导致了 防御性代谢物的发展和这些防御性代谢物可以被重新用于治疗 人类感染的可能性。我们的第一个长期目标是建立卵块微生物区系，作为不同种类的宿主 细菌共生体，然后利用这些共生体构建天然产物组分文库。这个分数库 已经在各种生物检测中进行了筛选，最初的重点是抗感染和免疫调节 每一组分的分析和天然产物成分正在用创新的代谢组学进行分析 技术、基于核磁共振的MADByTE和基于质谱学的GNPS。主动型 这些成分将被阐明，它们的生物合成基因簇将被识别，并在活体啮齿动物身上进行评估。 模特。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作为研究 已经揭示在典型的实验室条件下只产生一小部分代谢物(&lt；25%)。 使用基于社区的共培养技术和利用收集的卵块的创新技术 将使我们能够复制生态环境中发生的许多化学相互作用，这些化学相互作用是 已知在调节这些沉默的代谢物中起着重要作用。 总体而言，我们提议的研究计划将通过建立海洋卵块来广泛影响该领域 是新奇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 针对未得到满足的和日益频繁的疾病。

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.