Biofilm Dissemination in Staphylococcus aureus

金黄色葡萄球菌中的生物膜传播

• 批准号: 8433953
• 负责人: Mohamed Omar Elasri
• 金额: $ 43.95万
• 依托单位: UNIVERSITY OF SOUTHERN MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8433953
• 关键词: Abscess; Acetylglucosamine; Acute suppurative arthritis due to bacteria; Adherence; Aerobic; Animal Model; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Area; Attention; Bacteria; Biomass; Caenorhabditis elegans; Catheters; Cell Death; Cells; Clinical; Collaborations; Communities; Complement; Complex; Confocal Microscopy; DNA; Daptomycin; Defect; Development; Genes; Goals; Growth; Host Defense; Human; Image Analysis; Immune response; Implant; In Vitro; Infection; Inflammation; Lead; Location; Maps; Measures; Medical Device; Microbial Biofilms; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Mutation; Nosocomial Infections; Pathogenesis; Pattern; Physiological; Play; Predisposition; Proteins; Proteomics; Regulation; Role; Sepsis; Site; Staging; Staining method; Stains; Staphylococcus aureus; Structure; Surface; Testing; Time; Tissues; Virulence; Virulence Factors; combat; conventional therapy; design; experience; extracellular; in vivo; insight; methicillin resistant Staphylococcus aureus; mortality; mutant; pathogen; public health relevance; subcutaneous; therapeutic target

DESCRIPTION (provided by applicant): Staphylococcus aureus is a versatile pathogen that causes a wide variety of infections. In addition to its large arsenal of virulence factors, S. aures can grow in biofilm communities that are recalcitrant to antibiotic treatment and host defenses. It is estimated that 80% of S. aureus hospital infections are associated with biofilm. This important aspect of staphylococcal growth and infection has received increased attention, yet we still do not fully understand the molecular mechanisms behind it. Biofilm development can generally be divided into four stages: adherence, accumulation, maturation and dispersion. Mature staphylococcal biofilms are characterized as bacterial communities encased in complex structures comprised of extrapolymeric substances that include extracellular DNA (eDNA) released from active cell death. Biofilm communities are metabolically heterogeneous and the physiological state of each cell is dictated by its location within the different environmental niches (e.g. aerobic, anaerobic). Cells are also actively released from the biofilm, which allows the infection to disseminate to other areas in the host. Previously we have characterized a new gene, msa that is involved in regulation of virulence and biofilm development. In this application, we will test the hypothesis that msa plays a key role in biofilm maturation and/or dispersion by regulating structuring and dispersion factors both in vitro and in vivo. We also hypothesize that the structural defects in biofilm caused by mutation of msa will lead to reduced pathogenic impact in biofilm-associated infections and increased clearance by the host. Finally, since the ultimate goal of this study is to exploit msa as a therapeutic target to enhance conventional therapy, we will examine the impact of msa on biofilm susceptibility to antibiotic treatment in vivo. We have developed two specific aims to test this hypothesis: 1) Define the role of msa in biofilm development in three representative clinical isolates. We will examine the maturation and dispersion stages of biofilm using confocal microscopy and proteomics. We will also map out the expression of msa within biofilm. 2) Define the role of msa in biofilm-associated infections, host responses and susceptibility to antibiotics using a murine model. Findings from this study will lead to development of anti-biofilm therapies that will be critical to combat recalcitrant infections.

描述（由申请人提供）：金黄色葡萄球菌是一种多功能病原体，会引起多种感染。除毒力因子的大量武器库外，S. Aures还可以在抗生素治疗和宿主防御的生物膜群落中生长。它 估计有80％的金黄色葡萄球菌医院感染与生物膜有关。葡萄球菌生长和感染的这一重要方面受到了越来越多的关注，但我们仍然没有完全了解其背后的分子机制。生物膜发育通常可以分为四个阶段：依从性，积累，成熟和分散。成熟的葡萄球菌生物膜的特征是被包含在复杂结构中的细菌群落，该结构由外聚合物物质组成，包括从活性细胞死亡中释放出的细胞外DNA（EDNA）。生物膜群落在代谢上是异质性的，每个细胞的生理状态由其在不同环境壁ni（例如有氧，厌氧）中的位置决定。细胞也从生物膜中积极释放，这使感染可以传播到宿主中的其他区域。以前，我们表征了一种新基因，即涉及毒力和生物膜发育的调节。在此应用程序中 我们将通过调节体外和体内的结构和分散因子来检验MSA在生物膜成熟和/或分散体中起关键作用的假设。我们还假设，由MSA突变引起的生物膜中的结构缺陷将导致致病性影响与生物膜相关感染的病原影响减少，并增加宿主的清除率。最后，由于这项研究的最终目的是利用MSA作为增强常规疗法的治疗靶点，因此我们将研究MSA对体内生物膜对抗生素治疗的易感性的影响。我们开发了两个特定的目的来检验这一假设：1）定义MSA在三种代表性临床分离株中生物膜发育中的作用。我们将使用共聚焦显微镜和蛋白质组学检查生物膜的成熟和分散阶段。我们还将在生物膜中绘制MSA的表达。 2）使用鼠模型定义了MSA在生物膜相关感染，宿主反应和对抗生素的易感性中的作用。这项研究的发现将导致抗生物膜疗法的发展，这对于对抗顽固感染至关重要。