Database designed novel anti-MRSA peptides

描述（由申请方提供）：耐甲氧西林金黄色葡萄球菌（MRSA）USA 300代表一个遗传相关菌株的进化枝，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。每年死于MRSA的人数正在迅速增加，已经超过了艾滋病毒/艾滋病。因此，迫切需要开发针对MRSA的新治疗方法。天然存在的抗微生物肽是多年来一直保持其效力的通用宿主防御分子。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剂。APD促进了抗菌肽领域的研究和教育，特别是为该项目奠定了坚实的基础。基于我们的初步结果，我们假设，最关键的参数可以从APD中提取，作为设计和优化强效抗MRSA肽的基础，这些肽会对细菌膜造成损伤，导致细菌死亡并增强宿主防御。为了验证我们的假设，我们设计了以下具体目标：（1）确定基于APD的决定抗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应答基因的关键调节剂;（3）检查数据库设计的肽对S.体内金黄色葡萄球菌生物膜感染和免疫调节机制。为了实现这些目标，PI组建了一个强大的团队，提供在遗传，蛋白质和结构水平上了解宿主-病原体相互作用以及使用动物模型体内肽介导的免疫反应所需的补充专业知识。因为我们的数据库设计的化合物代表了一种新的抗MRSA策略，可以有效地消除耐药的S。金黄色葡萄球菌USA 300在体外和体内，这项创新研究的结果有很大的潜力，提供有效的抗MRSA药物，使患者受益。

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.