Chemical Biology of Microbial Interspecies Signaling

微生物种间信号传导的化学生物学

• 批准号: 8370105
• 负责人: Roberto G. Kolter
• 金额: $ 39.72万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8370105
• 关键词: Affect; Antibiotic Resistance; Antibiotics; Antineoplastic Agents; Appearance; Bacteria; Bioinformatics; Biological Assay; Biological Factors; Biology; Chemicals; Chemistry; Clinical; Coculture Techniques; Development; Discipline; Ecology; Effectiveness; Environment; Enzymatic Biochemistry; Future; Genetic; Genome; Habitats; Image; Immunosuppressive Agents; Individual; Knowledge; Lead; Mass Spectrum Analysis; Mediating; Medicine; Methodology; Microbe; Modeling; Modern Medicine; Nature; Organism; Penicillins; Phase; Physiology; Research; Role; Signal Transduction; Signaling Molecule; Surveys; Therapeutic; Therapeutic Agents; design; interdisciplinary approach; liquid chromatography mass spectrometry; microbial; microorganism; microorganism interaction; nano-string; novel strategies; small molecule

DESCRIPTION (provided by applicant): Many therapeutic agents in use today are small molecule natural products produced by bacteria. While their use in clinical settings has been a boon for medicine, the functions that these molecules serve for the producing organisms are not well understood. This gap in knowledge may hinder efforts at discovering new compounds that may be developed into effective therapeutics in the future. Initially thought to serve primarily as agents of mutual destruction, we now recognize that many microbial products serve as signals that microbes sense in order to adapt to their environment. This ecological perspective of the role of natural products led to the development of our central hypothesis: Bacteria synthesize and secrete a large number of small signaling molecules that affect the physiology of other microbes that occupy the same habitat. This general hypothesis drives our proposed research. But the lines of experimentation we follow are also discovery-driven; over the past few years we have discovered new small molecules that mediate diverse interspecies interactions in the microbial world. In the initial phase of this project, we validated the main concept that studying the chemical biology of interspecies interactions can lead to the discovery of new small molecule natural products. As before, we will continue to follow approaches that meld the disciplines of microbial ecology, physiology, and genetics, with enzymology, bioinformatics, and small molecule chemistry. We now aim to take this multidisciplinary approach to the next level by raising the scale of our screens and increasing the throughput of our compound characterization. Specifically, we will pursue research along three directions aims: (i) We will carry out high-throughput, broad spectrum screens to discover molecules mediating interspecies interactions. (ii) We will investigate specific ecological microbial interactions to discover molecules that mediate them. (iii) We will carry out pair-wise co-cultures of actinomycete strains whose genomes have been sequenced to carry out genome assisted compound discovery. Throughout our analyses, we will use diverse methodologies ranging from Nanostring assays of transcriptional effects to high-throughput liquid chromatography/mass spectrometry and imaging mass spectrometry in order to characterize the nature of the interactions and to define the molecules involved. PUBLIC HEALTH RELEVANCE: The development of antibiotics as therapeutics is one of the key accomplishments of modern medicine. Penicillin (the first antibiotic to be intensively used) and many other antibiotics, many anti-cancer agents, and many immunosuppressants, are molecules produced by microorganisms, they are thus called small molecule natural products. Unfortunately, the appearance of antibiotic resistant bacteria has diminished the effectiveness of existing antibiotics and there is always a great need to discover more of these molecules; the proposed research aims at discovering new such molecules by studying the effects they have in mediating interactions among microbes.

描述（由申请人提供）：当今使用的许多治疗剂是由细菌产生的小分子天然产物。虽然它们在临床环境中的使用为医学带来了福音，但这些分子对生产生物体的功能尚不清楚。这种知识差距可能会阻碍发现未来可能开发成有效疗法的新化合物的努力。最初认为主要用作 相互毁灭的媒介，我们现在认识到，许多微生物产物充当微生物感知的信号，以适应其环境。这种对天然产物作用的生态视角导致了我们中心假设的发展：细菌合成并分泌大量小信号分子，影响占据同一栖息地的其他微生物的生理机能。这个一般假设推动了我们提出的研究。但我们遵循的实验路线也是由发现驱动的。在过去的几年里，我们发现了介导微生物世界中不同种间相互作用的新小分子。在该项目的初始阶段，我们验证了主要概念，即研究种间相互作用的化学生物学可以导致新的小分子天然产物的发现。和以前一样，我们将继续遵循将微生物生态学、生理学和遗传学与酶学、生物信息学和小分子化学学科相融合的方法。我们现在的目标是通过扩大屏幕规模和提高化合物表征的通量，将这种多学科方法提升到一个新的水平。具体来说，我们将沿着三个方向进行研究：（i）我们将进行高通量、广谱筛选，以发现介导物种间相互作用的分子。 （ii）我们将研究特定的生态微生物相互作用，以发现介导它们的分子。 (iii) 我们将对基因组已测序的放线菌菌株进行配对共培养，以进行基因组辅助化合物发现。在整个分析过程中，我们将使用多种方法，从转录效应的纳米串测定到高通量液相色谱/质谱和成像质谱，以表征相互作用的性质并定义所涉及的分子。 公共卫生相关性：抗生素作为治疗药物的发展是现代医学的关键成就之一。青霉素（第一个被广泛使用的抗生素）和许多其他抗生素、许多抗癌剂和许多免疫抑制剂都是由微生物产生的分子，因此被称为小分子天然产物。不幸的是，抗生素耐药性细菌的出现削弱了现有抗生素的有效性，因此始终非常需要发现更多此类分子；拟议的研究旨在通过研究它们在介导微生物之间相互作用中的作用来发现新的此类分子。