Ecological Leads for Drug Discovery from Marine Organisms

助理课程2 项目摘要 副计划2的目标是利用生态学的见解来指导新的天然产品的发现 对发展中国家和联合国至关重要的一组目标疾病具有生物活性， States.在复杂的环境中，如近岸海洋栖息地，次生代谢已经进化到 数十亿年来，为了应对生物体面临的强烈选择压力， 生存和繁殖。特别是，热带珊瑚礁拥有多种微生物，藻类， 无脊椎动物使用化学线索和化学防御作为语言， 在物种内。在调节生态相互作用中起关键作用的小有机分子很强 针对细菌、真菌和寄生虫引起的传染病的新药候选物，此外， 癌症和神经系统疾病我们将探索研究不足的珊瑚礁生物，包括稀有物种， 海藻和无脊椎动物以及与海藻和珊瑚表面相关的微生物。我们将应用 生态分析揭示新的次生代谢，扩展我们以前的工作测试， 通过增加微生物覆盖和挑战试验， 寻找富含化学物质的微生物，专门作为病原体，互利主义者，或产生独特的 由于复杂的生态相互作用而产生的次级代谢物。对先导药物分子的追求将基于 在一系列与传染病有关的药理学筛选中优先考虑活动，热带被忽视 疾病、癌症和神经变性和CNS病症。新天然产物结构的鉴定 将利用现代光谱技术，导致临床前研究。一旦我们的目标实现，我们将 为生物医学研究界贡献了新的药物线索;揭示了新的分子 支架和受体-配体相互作用的化学和化学生物学社区;学到了新的 关于海洋宏观微生物和微生物中化学线索和化学防御作用的课程; 应用新的代谢组学和代谢网络方法研究海洋生物的次生代谢 生物;并在美国和南太平洋培养了一代科学人员。

Associate Program 2 Project Summary The goal of Associate Program 2 is to use ecological insights to guide the discovery of novel natural products with biological activity against a targeted group of diseases critical to developing nations and to the United States. In complex environments such as near-shore marine habitats, secondary metabolism has evolved over billions of years in response to intense selection pressure on organisms to solve critical challenges associated with survival and reproduction. In particular, tropical coral reefs host diverse microorganisms, algae, and invertebrates that use chemical cues and chemical defenses as a language driving interactions among and within species. Small organic molecules that are critical in mediating ecological interactions are strong candidates for new medicines targeting infectious disease caused by bacteria, fungi, and parasites, in addition to cancer and neurological disorders. We will explore understudied coral reef organisms including rare species of marine algae and invertebrates and microbes associated with algal and coral surfaces. We will apply ecological assays to uncover novel secondary metabolism, extending our previous work testing for antimicrobial, antiherbivore, and allelopathic compounds by adding microbial overlay and challenge assays to seek chemically rich microbes specialized as pathogens, mutualists, or commensals that produce unique secondary metabolites due to complex ecological interactions. Pursuit of lead drug molecules will be based on prioritized activity in a series of pharmacological screens relevant to infectious disease, tropical neglected disease, cancer, and neurodegenerative and CNS disorders. Identification of novel natural product structures will utilize modern spectroscopic techniques, leading to preclinical studies. Once our aims are met, we will have contributed novel pharmaceutical leads to the biomedical research community; revealed new molecular scaffolds and receptor-ligand interactions to the chemistry and chemical biology communities; learned new lessons on the roles of chemical cues and chemical defenses among marine macro- and microorganisms; applied new metabolomic and metabolic networking approaches to studying secondary metabolism in marine organisms; and trained a generation of scientific personnel in the U.S. and the South Pacific.