Thrombosis and Hemostasis in Host Defense from Bacterial Infection

宿主防御细菌感染时的血栓形成和止血

• 批准号: 8450253
• 负责人: Hongmin Sun
• 金额: $ 42.19万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450253
• 关键词: Affect; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Attenuated; Bacteria; Bacterial Infections; Biological Assay; Biological Process; Blood Coagulation Disorders; Cause of Death; Communicable Diseases; Data; Development; Fibrinogen; Fostering; Gene Chips; Genes; Glomerulonephritis; Growth; Hemostatic function; Host Defense; Human; Infection; Kanamycin Resistance; Modeling; Molecular Bank; Molecular Genetics; Mus; Northern Blotting; Pathogenesis; Pathogenicity; Plasminogen; Prevalence; Public Health; Publishing; Reagent; Reporting; Research Personnel; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Rheumatic Fever; Role; Streptococcal Infections; Streptococcus pyogenes; Streptokinase; Structure-Activity Relationship; System; Testing; Therapeutic Agents; Thrombosis; Time; Tissues; Transgenic Mice; United States National Institutes of Health; Virulence; Virulence Factors; antimicrobial; antimicrobial drug; base; design; high throughput screening; in vivo; infectious disease treatment; inhibitor/antagonist; killings; molecular imaging; novel; novel therapeutics; pathogen; pressure; programs; promoter; resistant strain; screening; tool

Seeinstructions): The widespread occurrence of antibiotic resistance among bacteria is causing increasing concern as a major threat to public health. Current antibiotics cause death or growth arrest in the target bacteria. As a result, antibiotic use exerts strong selective pressure to favor antibiotic resistant strains. Novel antimicrobial reagents that suppress pathogen virulence without selecting for antibiotic resistance provide a promising alternative approach for treatment of infectious diseases. Group A Streptococcus (GAS) is an important human pathogen affecting millions of people globally each year. The streptokinase (SK) is a major GAS virulence factor that activates human plasminogen. In our previous studies, we have established the streptokinase/plasminogen interaction as a critical factor in GAS pathogenesis. We propose to take advantage of this observation and design novel antimicrobial reagents for the treatment of GAS infection. In the preliminary study, we has screened 55,000 small compounds for inhibitors of SK expression and 20 candidate hit compounds have been identified. In specific aim I, the candidate compounds will befurther characterized and optimized to generate proper SK expression inhibitors for studying the roles of SK in GAS virulence. An additional high throughput screen of up to 500,000 more small compounds will be performed by taking advantage of the NIH Molecular Libraries and Imaging roadmap initiative. In specific aim II, Global effects of candidate compounds on GAS gene expressionwill be studied to provide clues for identification of the targets. GAS two-component system FasBCAX that has been demonstrated to regulate SK expression in published reports will be tested as prime candidate targets. In specific aim III,a number of murine GAS infection models established in our preliminary studies will be used to elucidate the effects of candidate compounds on GAS virulence in vivo. Data collected from the above studies will further our understanding of the contribution of SK to GAS infection and identify small compounds that can inhibit GAS virulence. As a result, alternative approach to treat bacterial infection by interfering with GAS virulence without unduly introducing selection pressure for resistance can be exploredto supplement antibiotic treatment. RELEVANCE (Seeinstructions): Group A Streptococcus (GAS) is an important human pathogen infecting millions of people. Streptokinase (SK) is one of the major GAS virulence factors. The overall objective of this proposal is to screen for small compounds to inhibit SK expression and explore these compounds both as tools to study GAS pathogenesis and as novel therapeutic reagents for treating GAS infections to supplement antibiotic treatment.

参见说明）： 抗生素耐药性在细菌中的广泛发生引起越来越多的关注，作为一种主要的 对公众健康的威胁。目前的抗生素导致目标细菌死亡或生长停滞。因此，在本发明中， 抗生素的使用产生了强大的选择压力，有利于抗生素抗性菌株。新型抗菌 抑制病原体毒力而不选择抗生素抗性的试剂提供了一种有希望的 治疗传染病的替代方法。A组链球菌（GAS）是一种重要的 人类病原体每年影响全球数百万人。链激酶（SK）是一种主要的GAS 激活人纤溶酶原的毒力因子。在我们以前的研究中，我们已经建立了 链激酶/纤溶酶原相互作用是GAS发病机制中的关键因素。我们建议采取 本研究旨在利用这一观察结果的优势，设计新型抗微生物试剂用于治疗GAS感染。在 在初步研究中，我们筛选了55，000种SK表达抑制剂的小化合物和20种 候选命中化合物已经被识别。在具体目标I中，候选化合物将进一步 为研究SK在GAS中的作用， 毒性。将对多达500，000个小化合物进行额外的高通量筛选 通过利用NIH分子库和成像路线图倡议。在具体目标二中，全球 将研究候选化合物对GAS基因表达的影响，为鉴定GAS基因提供线索。 目标GAS双组分系统FasBCAX已被证明可调节SK表达， 已发表的报告将作为主要候选目标进行测试。在具体目标III中，许多鼠GAS 在我们的初步研究中建立的感染模型将用于阐明候选物的作用。 化合物对GAS体内毒力的影响。从上述研究中收集的数据将进一步加深我们的理解 SK对GAS感染的贡献，并确定可以抑制GAS毒力的小化合物。作为 结果，通过干扰GAS毒力来治疗细菌感染的替代方法， 引入耐药性的选择压力可以用来补充抗生素治疗。 相关性（参见说明）： A组链球菌（GAS）是一种重要的人类病原体，感染数百万人。链激酶 (SK)是GAS的主要毒力因子之一。这项建议的总体目标是筛选小 化合物抑制SK表达，并探索这些化合物作为研究GAS发病机制的工具 以及作为用于治疗GAS感染的新治疗剂以补充抗生素治疗。