Chemical Biology of Microbial Interspecies Signaling

微生物种间信号传导的化学生物学

• 批准号: 8512734
• 负责人: Roberto G. Kolter
• 金额: $ 38.42万
• 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/8512734
• 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.

描述（由申请人提供）：目前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应用对医学来说是一个福音，但这些分子为生产生物体服务的功能还不是很清楚。这种知识上的差距可能会阻碍人们发现新的化合物，而这些化合物可能在未来被开发成有效的治疗方法。最初被认为主要用作