Chemical biology of bacterial symbionts

项目总结/摘要 这个项目解决了生物学和医学的一个关键问题：发现小分子， 作为调节生物过程和/或开发成治疗剂的基础。的细菌 生活在与其他有机体-共生细菌-产生小分子来调节 与主人和其他社区成员的关系，研究人员刚刚开始认识到， 这些相互作用的普遍性和大量的生物活性小分子， 保持他们。该提案描述了三种不同的方法来获得这些小分子及其 生物功能。两个集中在特定的共生体，第三个集中在一个一般的战略，以筛选 体内毒力因子。 1.第一个目标集中在一个以前未被认识的生态位，细菌共生体， 蘑菇这一目标的动机起源于一个愿望，以了解进化的起源， 我们今天看到的多边共生--最初的二元共生。这种进化是否 无论这种情况是否正确，专注于这些细菌的想法导致了一些非常有趣的初步研究。 结果：具有氧化性多环化生物合成的肽的胰红蛋白系统产生了一个 刚性的、拉紧的最终产品。 2.第二个目标集中在植物的细菌共生体-单细胞藻类， 光合作用合成了世界上大约一半的氧气，并固定了等量的碳。他们还 参与了许多其他的全球元素周期。这些藻类需要细菌的帮助 共生体来实现这些功能。藻类和它们的细菌共生体正在重新分布， 气候变化的方式，我们不完全理解。其中一些藻类-细菌系统涉及 生产对人类健康有影响或潜在影响的分子。例如，一个 另一种会产生一种叫做软骨藻酸的健忘神经毒素， 表型-可能的胞质分裂抑制剂，可用于增殖性疾病。 3.许多参与复杂共生的生物活性分子仍然是不可见的， 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 由群落中另一个成员的宿主提供的代谢物，以及“生产”细菌 可能提供了一种酶。这些分子和过程将是不可见的标准 代谢组学或基因组学分析。我们已经开发了一种具有相对高通量的体内筛选 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.