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Mechanistic Studies on Staphylococcal Quorum Quenching Natural Products

葡萄球菌群体淬灭天然产物的机理研究

基本信息

批准号：
9096696
负责人：
Cassandra Leah Quave
金额：
$ 36.58万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9096696
关键词：
Abscess Acquired Immunodeficiency Syndrome Address Affect Animals Anti-Infective Agents Antibiotic Resistance Antibiotics Bacteria Biological Assay Biological Availability Bypass Cannabis sativa plant Cell Line Cessation of life Clinical Column Chromatography Communicable Diseases Community Healthcare Coupled Crude Extracts Cyclic Peptides Data Development Disease Dose Drug Design Drug Kinetics Enzymes Epithelium Europe European Evaluation Exhibits Exposure to Fagaceae Food Fractionation Fruit Generations Genetic Government Growth Half-Life Hemolysin High Pressure Liquid Chromatography Human Immune system Infection Infectious Skin Diseases Inflammation Intravenous Knock-out Lead Link Liquid substance Lung Mediating Medical Methods Modeling Monitor Mus Nasal Epithelium Natural Products Nature Output Pathogenicity Pathway interactions Persons Pharmaceutical Preparations Phenotype Plant Leaves Plants Process Production Property Proteins Proteomics Public Health RNAIII Regulator Genes Reporter Resistance Sampling Scheme Scientist Signal Transduction Skin Skin Tissue Soft Tissue Infections Source Specimen Staging Standardization Staphylococcus aureus System Testing Therapeutic Time Tissues Topical application Toxin Trees Virulence Work base combat cytotoxicity drug discovery drug metabolism efficacy evaluation efficacy testing forest improved in vitro Assay in vivo in vivo Model insight keratinocyte methicillin resistant Staphylococcus aureus microbial mouse model mutant novel strategies pathogen pressure prevent quorum sensing research study skin abscess success voucher

项目摘要

DESCRIPTION (provided by applicant): Staphylococcus aureus is a highly problematic pathogen. Rates of infection in both the community and healthcare setting are on the rise, and coupled with its highly antibiotic-resistant nature, this makes S. aureus a top public health concern. In fact, invasive methicillin-resistant S. aureus (MRSA) is responsible for more deaths in the USA than AIDS. Nevertheless, the number of new antibiotic leads in the pipeline is diminishing, and many scientists have put out a call for the discovery and development of a new class of drugs which could mediate microbial pathogenicity rather than growth and survival. The staphylococcal quorum-sensing pathway, controlled by the accessory gene regulator (agr) system, is a potential target for such anti-pathogenic drug discovery efforts, as it serves as a global regulator of staphylococcal virulence. Following extensive studies on the complementary and alternative medical (CAM) practices of southern Italians in the treatment of skin and soft tissue infection, over 100 plant samples were identified, collected, extracted, and examined for their anti-staphylococcal potential. Among the tests included was a screen for the inhibition of δ-hemolysin, a translational protein product of RNAIII, whose production is regulated through the agr quorum-sensing pathway. Extract 134, which is derived from a popular tree with edible fruits and medicinal leaves and bark, was found to exhibit a strong dose-dependent inhibition of δ-hemolysin at sub-inhibitory concentrations for growth. The dose-dependent quorum-quenching effects of Extract 134 were confirmed through the use of fluorescent genetic reporters for agr (types I-IV). This activity is important based upon previous animal studies with agr knockout mutants that show a diminished capacity to initiate and persist in a skin infection model. In the proposed study, we seek to improve our understanding of the mechanistic basis for Extract 134's quorum-quenching effects and evaluate the therapeutic relevance of such an anti-virulence therapy using in vivo models. The study will address four specific aims: 1) identification and structural elucidation of the active constituent(s) (or marker compounds for standardization) in Extract 134; 2) elucidation of the mechanism of action for the quorum-quenching effects observed; 3) determination of drug metabolism and pharmacokinetic parameters (DM/PK) of the bioactive constituent(s); and 4) evaluation of efficacy in treating S. aureus skin infection in a murine model.

描述（由申请人提供）：金黄色葡萄球菌是一种非常有问题的病原体。社区和卫生保健机构的感染率都在上升，再加上金黄色葡萄球菌具有高度抗生素耐药性，这使得金黄色葡萄球菌成为一个主要的公共卫生问题。事实上，在美国，侵袭性耐甲氧西林金黄色葡萄球菌（MRSA）造成的死亡人数比艾滋病还要多。然而，新抗生素的数量正在减少，许多科学家呼吁发现和开发一类新的药物，这些药物可以调节微生物的致病性，而不是生长和生存。葡萄球菌群体感应途径由辅助基因调控（agr）系统控制，是这种抗致病性药物发现工作的潜在靶标，因为它是葡萄球菌毒力的全球调控因子。在对意大利南部治疗皮肤和软组织感染的补充和替代医学做法进行广泛研究之后，确定、收集、提取和检查了100多个植物样本，以确定其抗葡萄球菌的潜力。其中包括筛选对δ-溶血素的抑制作用，δ-溶血素是RNAIII的一种翻译蛋白产物，其产生通过agr群体感应途径调节。萃取物134提取自一种常见的具有可食用果实和药用叶子和树皮的树木，发现在亚抑制浓度下对δ-溶血素有很强的剂量依赖性抑制。通过使用agr （I-IV型）的荧光遗传报告基因，证实了提取物134的剂量依赖性群体猝灭效应。这种活性是重要的，因为先前的agr敲除突变体的动物研究表明，在皮肤感染模型中，agr敲除突变体的启动和持续能力减弱。在拟议的研究中，我们试图提高我们对提取物134的群体猝灭作用的机制基础的理解，并利用体内模型评估这种抗毒治疗的治疗相关性。该研究将解决四个具体目标：1)鉴定和结构阐明提取物134中的有效成分（或用于标准化的标记化合物）；2)阐明了观察到的群体猝灭效应的作用机理；3)测定生物活性成分的药物代谢和药代动力学参数（DM/PK）；4)对金黄色葡萄球菌皮肤感染小鼠模型的疗效评价。