Post-transcriptional regulation of biofilm formation S. aureus

生物膜形成的转录后调控金黄色葡萄球菌

• 批准号: 8147498
• 负责人: KIMBERLY Kay JEFFERSON
• 金额: $ 6.34万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-29 至 2011-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8147498
• 关键词: Address; Affinity Chromatography; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Bacteria; Bacterial Adhesins; Binding; Binding Sites; Biological Assay; Carbohydrates; Carbon; Catheters; Cell membrane; Cells; Clinical; Communities; Complex; Confocal Microscopy; Crystallography; Deletion Mutation; Development; Electrophoretic Mobility Shift Assay; Emerging Communicable Diseases; Endocarditis; Exhibits; Gel; Gene Cluster; Genes; Genetic Transcription; Glucosamine; Glucose; Goals; Growth; Half-Life; Healthy People 2010; Immune system; Immunodominant Antigens; In Vitro; Infection; Investigation; Laboratories; Lead; Length; Link; Medical Device; Membrane; Microbial Biofilms; Modality; Molecular; Monitor; Names; Nosocomial Infections; Nucleotides; Organism; Osteomyelitis; Pathway interactions; Phagocytosis; Plasmids; Play; Polymers; Polysaccharides; Population; Post-Transcriptional Regulation; Production; Protein Binding; Proteins; RNA; RNA Binding; RNA-Binding Proteins; Recombinants; Refractory; Regulation; Relapse; Repression; Research; Research Personnel; Resistance; Roentgen Rays; Role; Sepsis; Series; Source; Staphylococcus aureus; Structure; Surface; Techniques; Therapeutic; Therapeutic Agents; Transcript; Translating; Translational Repression; Translations; UDP-glucosamine; Untranslated Regions; Uridine Diphosphate Glucose; Virulence; X-Ray Crystallography; antimicrobial; base; chemotherapy; fighting; genetic manipulation; human tissue; improved; mutant; novel; pathogen; prevent; programs; promoter

DESCRIPTION (provided by applicant): Staphylococcus aureus is one of the most common causes of nosocomial bloodstream infections and is also an important cause of endocarditis, osteomyelitis, and other infections. Antibiotic resistance in S. aureus is a serious clinical problem that is compounded by the ability of the organism to form a biofilm on human tissues and inserted medical devices such as catheters. Most strains of S. aureus are able, under the appropriate environmental conditions, to elaborate a surface-associated (3-1-6-linked polymer of N-acetyl-glucosamine (PNAG) that serves two significant virulence functions: 1. it functions as the major constituent of the biofilm exo-polymeric matrix and 2. it protects the bacteria from phagocytosis during infection. The development of a biofilm during infection often results in a bacterial population that is refractory to antimicrobial chemotherapy and can act as a smoldering nidus for relapsing infection. In addition, resistance to phagocytosis enables the bacteria to evade the immune system. Therefore, it is not surprising that the intercellular adhesin (ica) locus, which encodes four proteins, Ica A, IcaD, IcaB, and IcaC, that are involved in PNAG synthesis, appears to play a critical role in virulence. Current therapeutic modalities for S. aureus infections could be significantly improved by inhibiting the formation of a resistant biofilm. The long-term objective of this project is to characterize the regulation of PNAG elaboration and subsequent biofilm formation bv S. aureus. A thorough understanding of this pathway could lead to the identification of targets for anti-biofilm therapeutic agents to act svnergisticallv with conventional antibiotics. This addresses the Healthy People 2010 goal of fighting "Infectious Diseases and Emerging Antimicrobial Resistance" and goal 14-20 "Hospital Acquired Infections". We have isolated an RNA-binding protein that binds to ica transcript and appears to increase half-life of the RNA and inhibit translation. The immediate goal of this proposed project is to further characterize the post- transcriptional regulatory mechanism bv which this RNA-binding protein regulates ica expression and PNAG production. Short Description. Staphylococcus aureus is an important pathogen that can cause a variety of infections. Antibiotic resistance in S. aureus is common and the problem is compounded by its ability to form adherent, polysaccharide-encased communities called biofilms. The goal of our research is to characterize the mechanism by which biofilm formation is regulated in S. aureus. Understanding the mechanism of biofilm regulation could lead to the development of anti-biofilm therapies that would act synergistically with conventional antibiotics.

描述（由申请人提供）：金黄色葡萄球菌是医院内血流感染的最常见原因之一，也是心内膜炎、骨髓炎和其他感染的重要原因。S.金黄色葡萄球菌是一个严重的临床问题，该问题由于该生物体在人体组织和插入的医疗装置如导管上形成生物膜的能力而变得复杂。大多数S.金黄色葡萄球菌能够在适当的环境条件下精心制作N-乙酰基-葡糖胺（PNAG）的表面缔合的（3-1-6-连接的）聚合物，其提供两个重要的毒力功能：1.它作为生物膜外聚合物基质的主要成分，和2.它保护细菌在感染过程中不被吞噬。在感染期间生物膜的发展通常导致细菌群体对抗微生物化学疗法是难治的，并且可以充当复发性感染的阴燃病灶。此外，对吞噬作用的抵抗使细菌能够逃避免疫系统。因此，毫不奇怪，编码参与PNAG合成的四种蛋白质伊卡A、IcaD、IcaB和IcaC的细胞间粘附素（ica）基因座似乎在毒力中起关键作用。目前的治疗模式，S。金黄色葡萄球菌感染可以通过抑制耐药生物膜的形成而显著改善。该项目的长期目标是表征PNAG的制作和随后的生物膜形成的调节由S。金黄色。对这一途径的透彻理解可能导致抗生物膜治疗剂与常规抗生素协同作用的靶点的鉴定。这涉及到2010年健康人的目标，即抗击“传染病和新出现的抗菌素耐药性”和目标14-20“医院获得性感染”。我们已经分离出一种RNA结合蛋白，它与伊卡转录物结合，似乎可以增加RNA的半衰期并抑制翻译。本项目的近期目标是进一步研究这种RNA结合蛋白调控伊卡表达和PNAG产生的转录后调控机制。简短描述。金黄色葡萄球菌（Staphylococcus aureus）是一种重要的病原菌，可引起多种感染。S.金黄色葡萄球菌是常见的，并且该问题由于其形成粘附的、被多糖包裹的称为生物膜的群落的能力而变得复杂。我们的研究目的是描述S.金黄色。了解生物膜调节的机制可能会导致抗生物膜疗法的发展，这些疗法将与传统抗生素协同作用。