Thrombosis and Hemostasis in Host Defense from Bacterial Infection

请参阅说明)： 细菌中普遍存在的抗生素耐药性正引起人们越来越多的关注 对公众健康的威胁。目前的抗生素会导致目标细菌死亡或生长停滞。结果, 抗生素的使用施加了强大的选择压力，有利于抗生素耐药菌株。新型抗菌剂 抑制病原体毒力而不选择抗生素耐药性的试剂提供了一种有希望的 治疗传染病的另一种方法。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)是一种主要的气体 激活人类纤溶酶原的毒力因子。在我们之前的研究中，我们已经建立了 链激酶/纤溶酶原相互作用是GAS发病的关键因素。我们建议采取 利用这一观察优势，设计新型抗菌试剂用于气体感染的治疗。在……里面 在初步研究中，我们已经筛选了55,000个小分子化合物来抑制SK的表达，其中20个化合物 已经确定了候选的热门化合物。在特定的目标I中，候选化合物将进一步 鉴定和优化以产生适当的SK表达抑制物，以研究SK在GAS中的作用 致命性。将对多达500,000多个小化合物进行额外的高通量筛选 通过利用NIH分子图书馆和成像路线图倡议。在特定目标II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已被证明调节SK的表达 已发布的报告将作为主要候选目标进行测试。在特定目标III中，一些老鼠毒气 在我们的初步研究中建立的感染模型将被用来阐明候选药物的影响 化合物对气体的体内毒力。从上述研究中收集的数据将加深我们对 研究SK对气体感染的贡献，并找出可以抑制气体毒力的小分子化合物。作为一名 结果：通过干扰气体毒力而不过度治疗细菌感染的替代方法 引入耐药选择压力可作为抗生素治疗的补充。 相关性(请参阅说明)： A组链球菌(GAS)是一种重要的人类病原体，感染着数以百万计的人。链激酶法 (SK)是毒力最强的毒力因子之一。这项建议的总体目标是筛选小的 抑制SK表达的化合物及其作为研究GAS发病机制的工具 以及作为治疗气体感染的新型治疗试剂，以补充抗生素治疗。

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.