Marine symbiotic interactions for discovery of bioactive compounds

海洋共生相互作用发现生物活性化合物

基本信息

批准号：
9063428
负责人：
Eric W Schmidt
金额：
$ 29.23万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-02 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9063428
关键词：
Action Potentials Affect Anabolism Animals Anti-Bacterial Agents Antibiotics Automobile Driving Bacteria Bacterial Infections Basic Science Biological Biological Assay Biology Cells Chemicals Chemistry Development Disease Environment Eukaryotic Cell Evolution FDA approved Funding Goals Ion Channel Lead Libraries Malignant Neoplasms Marine Invertebrates Marines Methods Microbe Miniaturization Molecular Target Natural Products Natural Products Chemistry Neurologic Neurology New Agents Organism Pharmaceutical Preparations Pharmacologic Substance Principal Component Analysis Research Personnel Running Shapes Source Symbiosis System Testing Therapeutic Agents Time Universities Utah Wisconsin base carbon skeleton coastal water design drug development drug discovery human disease improved innovation metabolomics microbial nervous system disorder novel strategies oncology programs public health relevance receptor research study scaffold small molecule working group

项目摘要

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.

描述（由申请人提供）：几乎所有地球上的动物都与细菌相互作用。在许多情况下，在古老的共生物中，细菌已经进化出了特定的小分子天然产物，以与其宿主生物和其他竞争微生物相互作用。这些化合物可以异常具有生物活性，有些甚至是FDA批准的药物用于治疗癌症等疾病。这些分子可能与许多不同动物的分子靶标共同进化，这意味着它们是通过进化而选择的，以对动物产生功能影响。反过来，可以利用这些效果来创建新药。这些相互作用才被开始被理解，并代表了发现有潜力治疗人类疾病的药物的几乎未开发的水库。在这里，我们将对海洋共生系统进行基本实验，培养细菌，并发现和发展生物活性小分子。我们的重点将放在影响竞争细菌（抗生素）和宿主生物（影响真核细胞并可能用于神经病学或肿瘤学的分子）上的分子。我们将采用理性的，假设驱动的方法来理解和利用共生相互作用。在此提案中，我们将重点关注美国沿海水域的动物与细菌之间的关联。在那里，我们发现了特定的共生细菌，可以综合出意外多样化的新生物活性化合物。我们试图了解这些相互作用，同时获得新化合物作为治疗剂的进一步发展。我们的目标是：1）了解天然产品如何塑造共生相互作用。我们将专注于海洋无脊椎动物及其相关的可栽培细菌之间的特定相互作用。 2）从栽培细菌中发现新的天然产品。我们将使用代谢组学方法快速磨损以前未知的天然产品。到目前为止，这些化合物已被证明是非常活跃的，并包括带有新碳骨架的新化合物。我们将专注于威斯康星大学和犹他大学提供的创新抗生素和神经活动测定。我们还将开发可以更广泛筛选的库。 3）开发用于治疗人类疾病的天然产品。我们将结合化学和生物技术方法，以评估新发现的药物的承诺并将其推向应用。我们将从我们实验室中已经发现的一些铅化合物开始，然后为在该项目中发现的其他代理使用已建立的管道。