Database designed novel anti-MRSA peptides

数据库设计的新型抗 MRSA 肽

基本信息

批准号：
8728418
负责人：
GUANGSHUN WANG
金额：
$ 35.37万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-06 至 2014-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8728418
关键词：
AIDS/HIV problem Action Potentials Amino Acid Sequence Animal Model Apoptosis Bacterial DNA Biological Biology Biophysics Cessation of life Classification Communicable Diseases DNA Microarray Chip Data Databases Education Engineering Evaluation Frequencies Future Generations Genes Genetic Hospitals Host Defense Hydrophobicity Immune response In Vitro Indium Individual Infection Invaded Investigation Laboratories Lead Life Mediating Medical center Membrane Microbial Biofilms Modeling Mus Names Natural Immunity Nature Nebraska Outcome Patients Peptides Positioning Attribute Property Research Resistance Resources Scientist Skin Tissue Soft Tissue Infections Solid Source Staphylococcus aureus Structural Protein Structure System Testing Universities Update Virulence Factors Work antimicrobial antimicrobial peptide base combat community setting database design design immunoregulation in vivo innovation interest membrane model methicillin resistant Staphylococcus aureus microbial natural antimicrobial novel pathogen prevent public health relevance response structural biology three dimensional structure

项目摘要

DESCRIPTION (provided by applicant): Methicillin-resistant Staphylococcus aureus (MRSA) USA300 represents a clade of genetically related strains that are a major cause of skin and soft tissue infections in the hospital as well as the community settings in otherwise healthy individuals. The annual frequency of deaths from MRSA is rapidly increasing and has surpassed those caused by HIV/AIDS. Therefore, there is an urgent need to develop new treatments against MRSA. Naturally occurring antimicrobial peptides are universal host defense molecules that have retained their potency throughout the years. To effectively exploit these interesting compounds, we have been constructing, expanding, and updating the widely used Antimicrobial Peptide Database (APD; http://aps.unmc.edu/AP/main.html). This comprehensive database facilitates naming, classification, statistical analysis, search, prediction and design of novel antimicrobials with desired properties. The APD has advanced the research and education in the antimicrobial peptide field in general and laid a solid basis for this project in particular. Based on our preliminary results, we hypothesize that most critical parameters can be extracted from the APD as a basis for designing and optimizing potent anti-MRSA peptides that cause damage on bacterial membranes, leading to bacterial death and augmenting host defense. To test our hypothesis, we have designed the following specific aims: (1) To identify the critical parameters that determine potency of anti-MRSA peptides based on the APD; (2) To elucidate the critical modulator in anti-MRSA peptides that determines mechanism of action and potential bacterial response genes; and (3) To examine the efficacy of database-designed peptides against S. aureus biofilm infection in vivo and mechanisms of immune modulation. To accomplish these aims, the PI has assembled a strong team that provides complementary expertise needed to understand host-pathogen interactions at the genetic, protein, and structural level as well as peptide-mediated immune responses in vivo using animal models. Because our database-designed compounds represent a novel anti-MRSA strategy that effectively eliminated resistant S. aureus USA300 both in vitro and in vivo, the outcome of this innovative research has great potential in providing potent anti-MRSA agents that benefit patients.

描述（由申请人提供）：耐甲氧西林金黄色葡萄球菌 (MRSA) USA300 代表遗传相关菌株的一个分支，是医院以及社区环境中其他健康个体皮肤和软组织感染的主要原因。 MRSA 每年造成的死亡人数正在迅速增加，并且已经超过了艾滋病毒/艾滋病造成的死亡人数。因此，迫切需要开发针对MRSA的新疗法。天然存在的抗菌肽是通用的宿主防御分子，多年来一直保持其效力。为了有效地利用这些有趣的化合物，我们一直在构建、扩展和更新广泛使用的抗菌肽数据库（APD；http://aps.unmc.edu/AP/main.html）。这个综合数据库有助于命名、分类、统计分析、搜索、预测和设计具有所需特性的新型抗菌药物。 APD总体上推进了抗菌肽领域的研究和教育，特别是为本项目奠定了坚实的基础。根据我们的初步结果，我们假设可以从 APD 中提取最关键的参数，作为设计和优化强效抗 MRSA 肽的基础，这些肽会损害细菌膜，导致细菌死亡并增强宿主防御。为了检验我们的假设，我们设计了以下具体目标：（1）根据APD确定决定抗MRSA肽效力的关键参数； (2) 阐明抗MRSA肽中决定作用机制和潜在细菌反应基因的关键调节剂； (3) 研究数据库设计的肽对体内金黄色葡萄球菌生物膜感染的功效和免疫调节机制。为了实现这些目标，PI 组建了一支强大的团队，提供所需的补充专业知识，以了解遗传、蛋白质和结构水平上的宿主-病原体相互作用，以及使用动物模型了解体内肽介导的免疫反应。由于我们的数据库设计的化合物代表了一种新颖的抗 MRSA 策略，可在体外和体内有效消除耐药金黄色葡萄球菌 USA300，因此这项创新研究的成果在提供造福患者的有效抗 MRSA 药物方面具有巨大潜力。