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: 7796865
• 负责人: KIMBERLY Kay JEFFERSON
• 金额: $ 28.38万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796865
• 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（申请人提供）：金黄色葡萄球菌是院内血流感染最常见的原因之一，也是心内膜炎、骨髓炎等感染的重要原因。金黄色葡萄球菌的抗生素耐药性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器械（例如导管）上形成生物膜的能力而变得更加复杂。大多数金黄色葡萄球菌菌株能够在适当的环境条件下，形成表面相关的（3-1-6 连接的 N-乙酰氨基葡萄糖 (PNAG) 聚合物），它具有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，2. 它可以保护细菌在感染过程中免受吞噬作用。 感染期间的生物膜通常会产生对抗菌化疗耐药的细菌群，并且可能成为复发感染的闷烧病灶。此外，对吞噬作用的抵抗使细菌能够逃避免疫系统。因此，细胞间粘附素 (ica) 位点编码 Ica A、IcaD、IcaB 四种蛋白，这并不奇怪。 和 IcaC 参与 PNAG 合成，似乎在毒力中发挥着关键作用。通过抑制耐药生物膜的形成，可以显着改善目前金黄色葡萄球菌感染的治疗方式。该项目的长期目标是表征金黄色葡萄球菌对 PNAG 精制和随后生物膜形成的调节。对该途径的透彻理解可以导致目标的识别 抗生物膜治疗剂与常规抗生素具有协同作用。这涉及“健康人 2010”抗击“传染病和新出现的抗菌素耐药性”的目标以及目标 14-20“医院获得性感染”。我们分离出了一种 RNA 结合蛋白，它与 ica 转录物结合，似乎可以延长 RNA 的半衰期并抑制翻译。近期目标是 该项目旨在进一步表征该 RNA 结合蛋白调节 ica 表达和 PNAG 产生的转录后调节机制。简短描述。金黄色葡萄球菌是一种重要的病原体，可引起多种感染。金黄色葡萄球菌的抗生素耐药性很常见，而且它能够形成粘附的、多糖包裹的群落（称为生物膜），从而使问题变得更加复杂。目标 我们研究的目的是表征金黄色葡萄球菌中生物膜形成的调节机制。了解生物膜调节机制可能会导致与传统抗生素协同作用的抗生物膜疗法的发展。