Chemical biology of bacterial symbionts

细菌共生体的化学生物学

• 批准号: 9751781
• 负责人: Jon Clardy
• 金额: $ 41.55万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-09 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751781
• 关键词: Address; Algae; Anabolism; Area; Bacteria; Basic Science; Bioinformatics; Biological; Biological Models; Biological Process; Biology; Burkholderia; Carbon; Chemicals; Chemistry; Cleaved cell; Coculture Techniques; Communicable Diseases; Communities; Complex; Coupled; Culture Media; Cytokinesis; Detection; Diatoms; Disease; Elements; Enzymes; Etiology; Eukaryota; Fatty Acids; Genomics; Health; Human; Immune System Diseases; Insecta; Investigation; Laboratories; Life; Logic; Malignant Neoplasms; Marines; Mediating; Medical; Medicine; Methods; Molecular; Motivation; Neurotoxins; Organism; Oxygen; Pathogenicity; Peptides; Pharmaceutical Preparations; Phenotype; Photosynthesis; Planet Earth; Planets; Plants; Polyploidy; Process; Production; Recording of previous events; Regulation; Research; Research Personnel; Role; Signal Transduction; Structure; Symbiosis; System; Taxonomy; Testing; Therapeutic Agents; Virulence Factors; climate change; domoic acid; functional genomics; fungus; gut microbiome; high throughput screening; improved; in vivo; inhibitor/antagonist; member; metabolomics; microbial; pathogenic bacteria; population survey; prototype; small molecule; sugar; symbiont

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.

项目摘要/摘要 该项目解决了生物学和医学的关键问题：发现可以 作为控制生物过程和/或发展为治疗剂的基础。细菌 与其他生物（共生细菌）密切相关 - 产生小分子以调节 与他们的主人和其他社区成员的关系，研究人员刚刚开始欣赏 这些相互作用的普遍性以及所需的大量生物活性小分子 维护它们。该建议描述了访问这些小分子及其的三种不同方法 生物功能。两个重点是特定符号，第三个侧重于筛选的一般策略 体内病毒因素。 1。第一个目的侧重于先前未识别的生态位，是细菌的符号 蘑菇。这个目标的动机起源于了解理解进化起源的愿望 我们今天看到的多边符号 - 原始二进制符号。是否进化 场景是正确的，专注于这些细菌的想法导致了一些非常有趣的初步 结果：具有氧化多环化物生物合成的宠物的胰纤维蛋白系统，产生了 刚性，紧张的最终产品。 2。第二个目标重点是植物的细菌符号 - 单细胞藻类 光合作用大约是世界氧气的一半，并固定了相等数量的碳。他们也是 参加许多其他全球元素周期。这些藻类需要其细菌的帮助 符合这些功能的共生体。藻类及其细菌符号由于 气候变化我们不完全理解的方式。这些藻类细菌系统中的一些涉及 产生具有影响或潜在影响人类健康的分子。作为例子，一个 制作一种称为domoic酸的健忘神经毒素，另一个是诱导多倍体的因素 表型 - 可能可用于增殖疾病的可能细胞因子抑制剂。 3。参加复杂符号的许多生物活性分子仍然是看不见的 我们当前的发现方法。例如，活性分子可能是由不寻常的 由另一个社区成员和“生产”细菌提供的代谢产物 也许提供单个酶。这些分子和过程对于标准是看不见的 代谢组学或基因组分析。我们已经开发了一个体内屏幕，吞吐量相对较高 这可以帮助识别此类过程，而第三个特定目标则处理一些早期的概念证明 屏幕的应用。

项目成果

Quinones are growth factors for the human gut microbiota.

• DOI: 10.1186/s40168-017-0380-5
• 发表时间: 2017-12-20
• 期刊: Microbiome
• 影响因子: 15.5
• 作者: Fenn K;Strandwitz P;Stewart EJ;Dimise E;Rubin S;Gurubacharya S;Clardy J;Lewis K
• 通讯作者: Lewis K