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Therapeutic potential of Enterococcus faecalis bacteriophage phiEf11

粪肠球菌噬菌体phiEf11的治疗潜力

基本信息

批准号：
7938372
负责人：
Roy H. Stevens
金额：
$ 42.04万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7938372
关键词：
Antibiotic Resistance Antibiotic Therapy Antibiotics Applications Grants Bacteremia Bacteria Bacteriophages Biological Cells Chromosomes Custom Cytolysis DNA Dental Effectiveness Endocarditis Endodontically-Treated Tooth Endodontics Engineering Enterococcus faecalis Frequencies Future Genes Genome Growth Health Human Immunity Infection Infection Control Lysogeny Lytic Lytic Phase Medical Mutate Oral Manifestations Organism Organism Strains Pathway interactions Periapical Periodontitis Periodontitis Repression Resistance Sequence Analysis Site Technology Testing Therapeutic Therapeutic Agents Tooth structure Toxin Urinary tract infection Viral Genome Virulent Virus antimicrobial antimicrobial drug base cell killing design genetic element in vivo killings mutant novel strategies pathogen periapical public health relevance superinfection viral DNA

项目摘要

DESCRIPTION (provided by applicant): The emergence of Enterococcus faecalis as a significant human pathogen, with many strains becoming resistant to antibiotics emphasizes the need to develop new and effective means of controlling infections by these organisms. An alternative approach to antibiotics for treating E. faecalis infections is the use of E. faecalis-specific bacterial viruses (bacteriophages) that can lyse and kill cells of these bacteria in the course of a normal lytic infective cycle. To be usable for bacteriophage therapy a bacterial virus must be free of any undesirable genes, such as genes for toxins or antibiotic resistance, and not be capable of lysogeny, an infection pathway of temperate bacteriophages where the viral DNA remains largely dormant in the infected cell, either as an integrated unit within the host chromosome or as a self-replicating extra-chromosomal genetic element within the cell. Recently, we isolated a bacteriophage, which infects strains of E. faecalis. Our sequencing and analysis of the bacteriophage DNA found it to be free of any detectable toxin-related genes, however, as a temperate bacteriophage, it would not be suitable as a therapeutic agent in its wild type state. To rectify this limitation, we plan to genetically engineer a virulent derivative of this virus that would be incapable of lysogeny. We will accomplish this by synthesizing a synthetic viral genome in which lysogeny-related genes are either deleted or mutated. In effect, we will custom design a viral genome to produce a synthetic virus that is optimally suited to function as a therapeutic antimicrobial agent. The synthetic virus that we will generate in this project will be screened for antimicrobial effectiveness against E. faecalis. PUBLIC HEALTH RELEVANCE: Enterococcus faecalis infections are becoming a major health problem, due to the increasing frequency of antibiotic resistance among strains of this organism. In this application, we propose to use synthetic genome technology to generate a derivative of bacteriophage phiEf11, a bacterial virus that we have previously isolated that will be an effective antimicrobial agent for treating these infections.

描述(申请人提供)：粪肠球菌作为一种重要的人类病原体出现，许多菌株对抗生素产生抗药性，这突显了开发新的有效方法来控制这些细菌感染的必要性。治疗粪肠球菌感染的抗生素的另一种方法是使用粪肠球菌特异的细菌病毒(噬菌体)，这种病毒可以在正常的裂解感染周期中裂解和杀死这些细菌的细胞。要用于噬菌体治疗，细菌病毒必须没有任何不良基因，如毒素或抗生素耐药性基因，并且不能溶原性，这是温带噬菌体的一种感染途径，病毒DNA在感染细胞中基本上保持休眠状态，要么作为宿主染色体内的一个整合单位，要么作为细胞内自我复制的染色体外遗传元件。最近，我们分离到了一株感染粪肠球菌的噬菌体。我们对噬菌体DNA的测序和分析发现，它不存在任何可检测到的毒素相关基因，但作为一种温和的噬菌体，它在野生型状态下不适合作为治疗剂。为了纠正这一限制，我们计划从基因上设计一种这种病毒的毒力衍生品，它将不能溶原性。我们将通过合成一个与溶源相关的基因被删除或突变的合成病毒基因组来实现这一点。实际上，我们将定制设计一个病毒基因组，以产生一种最适合作为治疗性抗菌剂发挥作用的合成病毒。我们将在这个项目中产生的合成病毒将被筛选出对粪肠球菌的抗菌效果。公共卫生相关性：粪肠球菌感染正在成为一个主要的健康问题，这是因为这种微生物的菌株对抗生素的耐药性越来越频繁。在这项应用中，我们建议使用合成基因组技术来产生噬菌体phiEf11的衍生物，这是我们之前分离的一种细菌病毒，将成为治疗这些感染的有效抗菌剂。