Chemical biology of bacterial symbionts

项目摘要/摘要 这个项目解决了生物学和医学的一个关键问题：发现可以 作为调节生物过程和/或发展为治疗剂的基础。细菌 生活在与其他生物--共生细菌--密切相关的环境中，产生小分子来调节 与它们的主人和其他社区成员的关系，研究人员刚刚开始意识到 这些相互作用的普遍性和大量具有生物活性的小分子需要 维护好它们。这项提案描述了三种不同的方法来访问这些小分子和它们的 生物功能。两个侧重于具体的共生，第三个侧重于筛选的一般战略 体内毒力因子。 1.第一个目标集中在以前未被认识到的生态位，即细菌共生体 蘑菇。这一目标的动机源于对了解人类进化起源的渴望。 我们今天看到的多边共生--原始的二元共生。无论这种进化 无论场景是否正确，关注这些细菌的想法导致了一些非常有趣的初步结果 结果：具有氧化多环化生物合成的胰红素多肽系统产生了 僵硬的、紧张的最终产品。 2.第二个目标是研究植物中的细菌共生体--能够 光合作用大约占世界氧气的一半，并固定等量的碳。他们也 参与许多其他的全球元素周期。这些藻类需要细菌的帮助 共生体来完成这些功能。藻类和它们的细菌共生体由于 气候变化的方式，我们并不完全理解。其中一些藻类-细菌系统涉及 对人类健康有影响或潜在影响的分子的生产。作为例子，有一个 产生一种叫做软骨藻酸的健忘症神经毒素，另一种产生一种诱导多倍体的因子 表型-一种可能对增殖性疾病有用的细胞质分裂抑制物。 3.许多参与复杂共生的生物活性分子仍然是看不见的 我们目前的发现方法。例如，一种活性分子可能是由一种不寻常的 由群落中另一成员的宿主提供的代谢物，以及“产生”细菌 可能提供了一种单一的酶。这些分子和过程对标准分子是不可见的 新陈代谢或基因组分析。我们已经开发出一种具有较高吞吐量的活体屏幕 这有助于识别这样的过程，第三个具体目标涉及一些早期的概念验证 屏幕的应用。

Project Summary/Abstract This project addresses a key issue for both biology and medicine: the discovery of small molecules that can serve as the basis for regulating biological processes and/or developing into therapeutic agents. Bacteria that live in close association with other organisms – symbiotic bacteria – produce small molecules to regulate the relations with their hosts and other community members, and researchers are just now beginning to appreciate the pervasiveness of these interactions and the vast array of biologically active small molecules needed to maintain them. This proposal describes three different approaches to access these small molecules and their biological functions. Two focus on specific symbioses, and the third focuses on a general strategy to screen for in vivo virulence factors. 1. The first aim focuses on a previously unrecognized ecological niche, the bacterial symbionts of mushrooms. The motivation for this aim originated in a desire to understand the evolutionary origins of the multilateral symbioses we see today – the original binary symbioses. Whether this evolutionary scenario is correct or not, the idea of focusing on these bacteria led to some very interesting preliminary results: the tryptorubin system of peptides with an oxidative polycyclization biosynthesis that creates a rigid, strained final product. 2. The second aim focuses on the bacterial symbionts of plants – the unicellular algae that photosynthesize roughly half of the world's oxygen and fix an equivalent amount of carbon. They also take part in many other global element cycles. These algae require the assistance of their bacterial symbionts to fulfill these functions. The algae and their bacterial symbionts are redistributing due to climate change in ways that we don't fully understand. Some of these algal-bacterial systems involve the production of molecules with impacts or potential impacts on human health. As examples, one makes an amnesic neurotoxin called domoic acid, and another makes a factor that induces a polyploidy phenotype – a likely cytokinesis inhibitor that could be useful for proliferative diseases. 3. Many of the biologically active molecules that take part in complex symbioses continue to be invisible to our current discovery methods. For example, an active molecule might be made from an unusual metabolite provided by the host of another member of the community, and the `producing' bacteria might be providing a single enzyme. These molecules and processes will be invisible to standard metabolomic or genomic analyses. We have developed an in vivo screen with relatively high throughput that can help identify such processes, and the third specific aim deals with some early proof of concept applications of the screen.