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Evaluation of Novel Antimicrobial Agents and a Novel Shuttle Vector

新型抗菌剂和新型穿梭载体的评价

基本信息

批准号：
7849914
负责人：
MARK R LILES
金额：
$ 18.08万
依托单位：
AUBURN UNIVERSITY AT AUBURN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7849914
关键词：
Anabolism Antibiotic Resistance Antibiotics Bacterial Artificial Chromosomes Biochemical Bioinformatics Biological Assay Biological Factors Chemical Structure Chemicals Chemistry Civilization Cloning Cloning Vectors Collection Communicable Diseases Communities Complex DNA Sequence Development Drug Industry Engineering Escherichia coli Eukaryotic Cell Evaluation Funding Future Genes Genetic Genomic Library Genomics Goals Gram-Negative Bacteria Health Human Incidence Infectious Agent Lead Libraries Liquid Chromatography Metagenomics Molecular Weight Pathway interactions Pharmacologic Substance Phylogenetic Analysis Plague Process Production Property Recombinants Relative (related person)Research Resources Shuttle Vectors Soil Structure Therapeutic Therapeutic Agents Toxic effect Type I Polyketide Synthase antimicrobial antimicrobial drug combat design expression cloning genetic analysis microbial community microorganism new technology next generation novel novel therapeutics pathogen pathogenic bacteria polyketide synthase public health relevance technology development vector

项目摘要

DESCRIPTION (provided by applicant): Antibiotics are our first line of defense against bacterial pathogens that have historically been a plague on human civilization. Increasingly, human pathogens that had been regarded as treatable infectious agents are becoming serious problems as a result of antibiotic resistance. There is an urgent need for novel antibiotics in the pharmaceutical pipeline, yet for many reasons the pharmaceutical industry has not invested heavily in the antibiotic discovery process. The best possible resource for antibiotic discovery is to explore microbial communities, where complex chemistries have naturally evolved. To access the complex chemistries from diverse microorganisms, this proposal uses a community genomic approach in which biosynthetic genes from diverse microorganisms are directly recovered from soils and expressed in E. coli or other bacterial hosts. A collection of fourty-four clones that produce antibiotic activity has already been isolated from these community genomic libraries. The proposed research will determine the chemical structure of antibiotic compounds from this collection, and determine the potency and any toxicity associated with these compounds. In addition to clones that express antibiotic activity, another collection of clones has been isolated that contain the genes for a specific class of natural product, the polyketides. Polyketide compounds have diverse structures, and diverse activities, such as antimicrobial and anticancer properties. A genetic analysis of polyketide biosynthesis pathways discovered from a soil microbial community library indicates that the 34 polyketide-containing clones are very different from known polyketide pathways. Our research efforts will transfer these polyketide pathways into a novel cloning vector, designed to allow transfer of genetic pathways between Gram-negative bacteria, and then genetic and bioassay screens will determine whether these polyketide pathways are expressed in different bacterial species. The results of this research will be a collection of lead candidate compounds with antimicrobial activity, novel polyketide biosynthetic pathways useful in engineering novel polyketide structures with therapeutic properties, an evaluation of a novel Gram- negative shuttle vector, and the next generation of microbial community genomic library for future development of this technology. PUBLIC HEALTH RELEVANCE: Antibiotics are critical to our ability to combat infectious disease, and especially in an era in which the incidence of antibiotic resistance is on the rise there is a need for discovery and development of clinically useful antibiotics. Using new technology for cloning and expressing genetic pathways from diverse microorganisms, a collection of clones that either produce an antimicrobial activity or encode a biosynthetic pathway have been isolated. The proposed research would evaluate this collection of clones at a genetic and biochemical level to determine which lead candidates have the best potential as novel therapeutic agents.

描述(申请人提供)：抗生素是我们对抗细菌病原体的第一道防线，而细菌病原体在历史上一直是人类文明的瘟疫。由于抗生素耐药性，被认为是可治疗的感染源的人类病原体正日益成为严重的问题。在制药管道中迫切需要新的抗生素，但由于许多原因，制药行业没有在抗生素发现过程中投入大量资金。发现抗生素的最好可能的资源是探索微生物群落，在那里复杂的化学物质已经自然进化。为了获得来自不同微生物的复杂化学成分，该建议使用了社区基因组方法，在这种方法中，来自不同微生物的生物合成基因直接从土壤中恢复并在大肠杆菌或其他细菌宿主中表达。已经从这些社区基因组文库中分离出了44个产生抗生素活性的克隆。拟议的研究将确定来自这一集合的抗生素化合物的化学结构，并确定与这些化合物相关的效力和任何毒性。除了表达抗生素活性的克隆外，还分离出了另一组克隆，这些克隆包含一种特定类别的天然产物聚酮的基因。聚酮类化合物具有不同的结构和不同的活性，如抗菌和抗癌性能。从土壤微生物群落文库中发现的聚酮生物合成途径的遗传分析表明，这34个含有聚酮的克隆与已知的聚酮途径有很大的不同。我们的研究工作将把这些聚酮途径转移到一个新的克隆载体中，旨在允许在革兰氏阴性细菌之间转移遗传途径，然后通过遗传和生物测定筛选来确定这些聚酮途径是否在不同的细菌物种中表达。这项研究的结果将是具有抗菌活性的主要候选化合物的集合，用于设计具有治疗性能的新型聚酮结构的新型聚酮生物合成途径，新型革兰氏阴性穿梭载体的评估，以及这项技术未来发展的下一代微生物群落基因组文库。公共卫生相关性：抗生素对我们抗击传染病的能力至关重要，特别是在抗生素耐药性发病率上升的时代，有必要发现和开发临床上有用的抗生素。利用克隆和表达不同微生物遗传途径的新技术，已经分离出一系列既能产生抗菌活性又能编码生物合成途径的克隆。这项拟议的研究将在遗传和生化水平上对这些克隆进行评估，以确定哪些候选先导最有潜力成为新的治疗剂。