Pan Genomic Discovery of Genes Toxic to Bacteria

对细菌有毒的基因的泛基因组发现

基本信息

批准号：
7635998
负责人：
EDWARD M RUBIN
金额：
$ 40.26万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
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：
2009-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7635998
关键词：
Acinetobacter baumannii Americas Anabolism Anti-Bacterial Agents Antibiotic Resistance Antibiotics Bacteria Biological Assay Buffers Candida albicans Candidate Disease Gene Cells Characteristics Chemicals Classification Clinic Clinical Cloning Code Communicable Diseases Communities DNA Data Data Set Databases Digestion Disease Enterococcus faecium Escherichia coli Functional RNA Funding Gene Cluster Generations Genes Genetic Transcription Genome Genomics In Vitro Incubated Individual Intercistronic Region Klebsiella pneumonia bacterium Marketing Methicillin Resistance Methods Methyltransferase Microbial Drug Resistance Microfluidics Modification Molecular Molecular Weight Mutate Mutation Northern Blotting Operon Pan Genus Pathway interactions Pattern Peptides Process Protein Biosynthesis Proteins Pseudomonas aeruginosa Public Domains Public Health RNA Reagent Research Infrastructure Research Personnel Resistance Reverse Transcriptase Polymerase Chain Reaction Sampling Screening procedure Sequence Analysis Site Societies Structure Testing Toxic effect Transcript Translations antimicrobial antimicrobial drug antimicrobial peptide bacterial resistance bactericide base clinically relevant comparative cost design drug development enzyme activity gene discovery gene function genome sequencing high throughput screening microbial microbial genome microorganism miniaturize mutant nanolitre novel novel strategies pathogen promoter public health relevance research study restriction enzyme

项目摘要

DESCRIPTION (provided by applicant): There is a growing need for new antimicrobial agents in the clinic. Antimicrobial drug resistance is rapidly spreading among pathogenic microorganisms of all types, but in sharp contrast to these emerging threats, the number of new antibiotics in the market is constantly decreasing, and the vast majority of new antibiotics represent modifications on chemical antibiotic classes that are already in clinical use. This proposal will utilize a method we recently developed for the discovery of thousands of genes toxic to bacteria, in order to identify potentially new classes of antibacterial agents. The approach is based on a by-product of the process of genome sequencing, where initial assemblies invariably contain gaps due to DNA fragments that cannot be successfully propagated in bacteria. In our pilot analysis of 79 finished microbial genomes, we discovered that many of these uncloneable gaps are caused by genes that are reproducibly toxic to E. coli, including novel antimicrobial peptides, toxic non-coding RNAs, and restriction enzymes. In this proposal we will analyze the gap content of approximately 1,500 finished microbial genomes, sampling all major phyla of the eubacterial and archaeal kingdoms, and identify a comprehensive set of an estimated ~40,000 genes toxic to E. coli. Toxic genes that are of unknown function will be evaluated in assays targeted at 1) identifying and studying antimicrobial peptides and novel antibiotic biosynthesis gene clusters 2) identifying and studying non-coding RNAs that are toxic to E. coli and 3) identifying and studying restriction enzymes that are present among the toxic genes. A public database of all genes toxic to E. coli and associated functional information from the 1,500 analyzed genomes will be developed. This database is anticipated to benefit a broad community of researchers studying antimicrobials, non-coding RNAs, restriction enzymes, and other gene functions resulting in toxicity to E. coli. PUBLIC HEALTH RELEVANCE: The rapid spread of antibiotics resistance among disease-causing bacteria forms a threat to public health. This proposal presents a new approach that facilitates the discovery of thousands of genes that are toxic to bacteria. This approach will be used to detect and develop new antimicrobial agents as well as study a new class of RNA molecules that are toxic to bacteria.

描述（由申请人提供）：诊所中对新的抗菌药物的需求越来越大。抗菌药物的耐药性正在迅速扩散到各种类型的致病微生物之间，但是与这些新兴威胁形成鲜明对比，市场上新的抗生素的数量不断减少，而绝大多数新的抗生素代表了对临床使用的化学抗生素的修饰。该建议将利用我们最近开发的一种方法来发现数千种对细菌有毒的基因，以鉴定潜在的新型抗菌剂。该方法基于基因组测序过程的副产品，在该过程中，由于无法在细菌中无法成功传播的DNA片段引起的初始组件总是包含间隙。在我们对79个成品微生物基因组的试验分析中，我们发现其中许多不可合委的间隙是由对大肠杆菌有毒的基因引起的，包括新型的抗菌肽，有毒的非编码RNA和限制性酶。在此提案中，我们将分析大约1,500个成品微生物基因组的间隙含量，对所有菌群和古细菌王国的所有主要门进行采样，并确定一组对大肠杆菌有毒的估计约40,000个基因。在以1）为目标的测定中评估未知功能的有毒基因，鉴定和研究抗菌肽和新型的抗生素生物合成基因簇2）识别和研究对大肠杆菌和3）毒性的非编码RNA，并研究限制限制性的enzymes，它们识别和研究毒性enzymes是有毒的毒性基因。将开发出所有有毒大肠杆菌的基因的公共数据库以及来自1,500个分析基因组的相关功能信息。预计该数据库将使研究抗菌剂，非编码RNA，限制酶和其他基因功能的广泛研究人员受益，从而导致对大肠杆菌的毒性。公共卫生相关性：抗生素耐药性在引起疾病的细菌中的迅速传播构成了对公共卫生的威胁。该提案提出了一种新方法，促进了成千上万对细菌有毒的基因的发现。该方法将用于检测和开发新的抗菌剂，并研究一类对细菌有毒的RNA分子。