Biofilms and Enterococcus faecalis Biology

生物膜和粪肠球菌生物学

• 批准号: 8038029
• 负责人: GARY M DUNNY
• 金额: $ 13.56万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8038029
• 关键词: Address; Antibiotic Resistance; Antimicrobial Resistance; Bacteria; Bacterial Infections; Behavior; Biological Process; Biology; Chemicals; Communities; Development; Endocarditis; Enterococcus; Enterococcus faecalis; Environment; Evolution; Foundations; Genes; Genetic; Genetic Determinism; Genetic Screening; Genetic Techniques; Genome; Genus staphylococcus; Gram-Positive Bacteria; Grant; Growth; Health; Heart Valves; Hospitals; Human; Implant; In Vitro; Infection; Investigation; Liquid substance; Maintenance; Medical; Medical Device; Microbial Biofilms; Organism; Patients; Physiology; Play Therapy; Process; Production; Proteins; Research; Research Personnel; Resistance; Resources; Role; Signal Transduction; Speed; Staging; Staphylococcus aureus; Structure; Surface; Testing; Vaccines; Vancomycin Resistance; Virulence; Work; antimicrobial; antimicrobial drug; base; clinically relevant; drug development; functional genomics; gene conservation; in vivo; inhibitor/antagonist; insight; microbial; novel; novel strategies; opportunistic infection agent; pathogen; pathogenic bacteria; prevent

DESCRIPTION (provided by applicant): Enterococcus faecalis iis one of the top three most frequently-isolated species from hospital- associated infections of compromised patients and it can cause a highly fatal form of endocarditis. The medical importance of the enterococci is enhanced by their high degree of inherent and acquired resistance to antimicrobial agents, and by their propensity to act as a major conduit for the spread of resistance genes to more highly-pathogenic organisms. Enterococci are commonly isolated from biofilms formed on implanted medical devices, and colonization and growth on heart valves is also considered a form of biofilm growth. The biofilm environment is a likely niche for transfer of high-level vancomycin resistance from enterococci to Staphylococcus aureus. We have used genetic screens to identify a large number of novel genetic determinants of biofilm formation in vitro, and ongoing studies provide increasing evidence for the importance of many of these determinants in biofilms formed in vivo during infections. Many previously un-characterized enterococcal biofim determinants show significant conservation in a variety of important pathogens; if they are functionally conserved, the products of these genes comprise a pool of potential targets for the development of chemical inhibitors or vaccines that could block biofilm formation during infections produced by many different pathogens . The results from the current grant provide a strong foundation for answering important basic questions about the biology of enterococcal biofilm formation, as well as new approaches to increasing our understanding of bacterial pathogenic mechanisms. The specific aims proposed to address these questions are to: 1. Use the information and resources from the present grant to identify critical signals and regulatory mechanisms involved in: a) the initial transition from planktonic to biofilm growth and, b) the subsequent development of the biofilm community. 2. Determine the effects of disruption of genes involved in enterococcal biofilm formation on virulence and identify functionally-conserved biofilm/virulence genes in S. aureus from the pool of novel biofilm determinants discovered in E. faecalis. 3. Identify determinants of biofilm-induced antibiotic resistance in the core genome of E. faecalis. PUBLIC HEALTH RELEVANCE: The research proposed in this application is focused on the process by which a bacterium called Enterococcus faecalis is able to grow on surfaces in a structure called a biofilm. In recent years it has become widely accepted that bacterial growth in biofilms causes major differences in the physiology and behavior of bacteria from that observed in liquid cultures, and that biofilm formation is involved in the production of many, if not most bacterial infections. Our research will employing genetic techniques to identify and characterize previously un-studied enterococcal genes that are important in biofilm formation, and to determine whether similar genes in another important pathogen, Staphylococcus aureus, have the same biological functions as the enterococcal genes. If there is functional conservation of these genes, it could speed the development of new antimicrobial drugs or vaccines.

描述（由申请人提供）：粪肠球菌是从受损患者的医院相关感染中最常见的三种分离菌种之一，它可引起高度致命的心内膜炎。肠球菌的医学重要性因其对抗菌剂的高度固有和获得性耐药性以及它们充当耐药基因向更高致病性生物体传播的主要渠道的倾向而得到增强。肠球菌通常从植入医疗设备上形成的生物膜中分离出来，心脏瓣膜上的定植和生长也被认为是生物膜生长的一种形式。生物膜环境可能是高水平万古霉素耐药性从肠球菌向金黄色葡萄球菌转移的利基。我们已经使用遗传筛选来鉴定体外生物膜形成的大量新的遗传决定因素，并且正在进行的研究提供了越来越多的证据，证明这些决定因素在感染期间体内形成的生物膜中的重要性。许多以前未表征的肠球菌生物膜决定簇在多种重要病原体中表现出显着的保守性；如果它们在功能上是保守的，那么这些基因的产物就构成了开发化学抑制剂或疫苗的潜在靶标，这些抑制剂或疫苗可以在许多不同病原体产生的感染过程中阻止生物膜的形成。当前资助的结果为回答有关肠球菌生物膜形成的生物学重要基本问题以及增加我们对细菌致病机制的理解的新方法提供了坚实的基础。为解决这些问题而提出的具体目标是： 1. 利用目前拨款中的信息和资源来确定涉及以下方面的关键信号和调节机制：a) 从浮游生长到生物膜生长的初始转变，b) 生物膜群落的后续发展。 2. 确定破坏肠球菌生​​物膜形成相关基因对毒力的影响，并从粪肠球菌中发现的新型生物膜决定簇中鉴定金黄色葡萄球菌中功能保守的生物膜/毒力基因。 3. 确定粪肠球菌核心基因组中生物膜诱导的抗生素耐药性的决定因素。 公共健康相关性：本申请中提出的研究重点是一种称为粪肠球菌的细菌能够在称为生物膜的结构的表面上生长的过程。近年来，人们普遍认为生物膜中的细菌生长导致细菌的生理和行为与液体培养中观察到的细菌的生理和行为存在重大差异，并且生物膜的形成涉及许多（如果不是大多数）细菌感染的产生。我们的研究将采用遗传技术来识别和表征以前未研究的对生物膜形成很重要的肠球菌基因，并确定另一种重要病原体金黄色葡萄球菌中的相似基因是否具有与肠球菌基因相同的生物学功能。如果这些基因的功能得到保护，则可以加速新抗菌药物或疫苗的开发。