Marine symbiotic interactions for discovery of bioactive compounds

描述(申请人提供)：几乎地球上的每一种动物都与细菌相互作用。在许多情况下，在古代共生的过程中，细菌进化出特定的小分子天然产物，与它们的宿主生物和其他相互竞争的微生物相互作用。这些化合物可能具有异常的生物活性，其中一些甚至是FDA批准的治疗癌症等疾病的药物。据推测，这些分子与它们的分子靶标在许多不同的动物中共同进化，这意味着它们是进化选择出来的，对动物有功能影响。反过来，这些效应可以被利用来创造新的药物。这些相互作用才刚刚开始被理解，并代表着一个几乎未被开发的储藏库，用于发现具有治疗人类疾病潜力的药物。在这里，我们将进行海洋共生系统的基础实验，培养细菌，发现和开发生物活性小分子。我们的重点将放在影响相互竞争的细菌(抗生素)和宿主有机体(影响真核细胞并可能在神经学或肿瘤学中使用的分子)的分子上。我们将采取理性的、假设驱动的方法来理解和利用共生相互作用。在这项提案中，我们将重点关注美国沿海水域中动物和细菌之间的联系。在那里，我们发现了特定的共生细菌，它们可以合成出人意料的各种新的生物活性化合物。我们寻求了解这些相互作用，同时获得新的化合物，以便进一步开发作为治疗剂。我们的目标是：1)了解天然产品如何形成共生互动。我们将专注于海洋无脊椎动物的不同门与其相关的可培养细菌之间的特定相互作用。2)从培养的细菌中发现新的天然产物。我们将使用代谢组学的方法来快速研磨以前未知的天然产品。到目前为止，这些化合物已被证明具有特别的活性，其中包括具有新碳骨架的新化合物。我们将重点介绍威斯康星大学和犹他大学提供的创新抗生素和神经活性分析方法。我们还将开发可以进行更广泛筛选的图书馆。3)开发用于治疗人类疾病的天然产物。我们将结合化学和生物技术方法来评估新发现的试剂的前景，并将它们推向应用。我们将从我们实验室中已经发现的几种先导化合物开始，然后使用已建立的管道为该项目中发现的其他试剂提供帮助。

DESCRIPTION (provided by applicant): Virtually every animal on Earth interacts with bacteria. In many cases, over the course of ancient symbioses bacteria have evolved specific small molecule natural products to interact with their host organisms and with other competing microbes. These compounds can be exceptionally bioactive, and some are even FDA-approved agents for treating diseases such as cancers. The molecules presumably co-evolved with their molecular targets in many different animals, meaning that they are selected by evolution to have functional effects on animals. In turn, these effects can be exploited for the creation of new pharmaceuticals. These interactions are just beginning to be understood and represent a virtually untapped reservoir for discovering agents with potential to treat human diseases. Here, we will perform fundamental experiments on marine symbiotic systems, cultivate bacteria, and discover and develop bioactive small molecules. Our focus will be on molecules that affect competing bacteria (antibiotics) and the host organism (molecules that affect eukaryotic cells and might have use in neurology or oncology). We will take a rational, hypothesis-driven approach to understanding and exploiting symbiotic interactions. In this proposal, we will focus on associations between animals and bacteria in US coastal waters. There, we have found specific symbiotic bacteria that synthesize unexpectedly diverse new, bioactive compounds. We seek to understand these interactions while obtaining new compounds for further development as therapeutic agents. Our aims are to: 1) Understand how natural products shape symbiotic interactions. We will focus on specific interactions between different phyla of marine invertebrates and their associated, cultivable bacteria. 2) Discover new natural products from cultivated bacteria. We will use a metabolomics approach to rapidly hone in on previously unknown natural products. These compounds have been proven so far to be exceptionally active and include new compounds with new carbon skeletons. We will focus on innovative antibiotic and neuroactivity assays available at University of Wisconsin and University of Utah. We will also develop libraries that can be more widely screened. 3) Develop natural products for application in treating human diseases. We will combine chemical and biotechnological approaches to assess the promise of newly discovered agents and to move them toward application. We will begin with a few lead compounds already discovered in our labs, then use the established pipeline for other agents discovered in this project.