Database designed novel anti-MRSA peptides

数据库设计的新型抗 MRSA 肽

• 批准号: 8817004
• 负责人: GUANGSHUN WANG
• 金额: $ 37.63万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-01 至 2019-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8817004
• 关键词: AIDS/HIV problem; Acinetobacter; Action Potentials; Amino Acid Sequence; Animal Model; Antibiotics; Antimalarials; Apoptosis; Attenuated; Bacterial DNA; Biological; Biology; Biophysics; Catheters; Cessation of life; Classification; DNA Microarray Chip; Data; Databases; Education; Engineering; Enterobacter; Enterococcus faecium; Evaluation; Frequencies; Future; Generations; Genes; Genetic; Healthcare; Host Defense; Hydrophobicity; Immune response; In Vitro; Indium; Infection; Invaded; Investigation; Klebsiella pneumonia bacterium; Laboratories; Lead; Life; Mediating; Medical center; Membrane; Microbial Biofilms; Modeling; Molecular; Mus; Names; Natural Immunity; Nebraska; Outcome; Patients; Peptides; Positioning Attribute; Prevention; Property; Pseudomonas aeruginosa; Research; Resistance; Resources; Scientist; Solid; Source; Staphylococcus aureus; Structural Protein; Structure; Superbug; Surface; System; Testing; United States; Universities; Update; Virulence Factors; Work; antimicrobial; antimicrobial drug; antimicrobial peptide; base; combat; database design; design; immunoregulation; in vivo; innovation; interest; killings; membrane model; methicillin resistant Staphylococcus aureus; microbial; mortality; natural antimicrobial; novel; pathogen; prevent; public health relevance; response; structural biology; three dimensional structure; tool

 DESCRIPTION (provided by applicant): The ESKAPE pathogens, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species are life- threatening superbugs due to their ability to escape the killing of traditional antibiotics. According to the Centers for Diseas Control and Prevention, these six types of bad bugs cause two thirds of the health care-associated infections, leading to 99,000 deaths annually in the United States. It is stunning that the annual frequency of deaths from Methicillin-resistant Staphylococcus aureus (MRSA) is comparable to those caused by HIV/AIDS. Therefore, there is an urgent need to develop new treatments against superbugs. 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). This comprehensive database facilitates naming, classification, statistical analysis, search, prediction and design of novel antimicrobials with desired properties. The APD tool has facilitated the research and education in the antimicrobial peptide field and laid a solid basis for this project. 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 antimicrobial 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 antimicrobial peptides and their mimics based on the APD; (2) To elucidate the critical modulator in antimicrobial peptides that determines mechanism of action and potential bacterial response genes; and (3) To examine the efficacy of database-designed peptides and their mimics against bacterial 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 antimicrobial strategy that effectively attenuated resistant superbugs both in vitro and in vivo, the outcome of this innovative research has great potential in providing potent antimicrobial agents that benefit patients.

 描述（申请人提供）： ESKAPE 病原体，包括屎肠球菌、金黄色葡萄球菌、肺炎克雷伯菌、鲍曼不动杆菌、铜绿假单胞菌和肠杆菌属，由于它们能够逃脱传统抗生素的杀灭，因此是危及生命的超级细菌。疾病控制与预防中心，这六种坏虫导致两个三分之一的医疗保健相关感染，导致美国每年 99,000 人死亡，令人震惊的是，每年因耐甲氧西林金黄色葡萄球菌 (MRSA) 造成的死亡人数与艾滋病毒/艾滋病造成的死亡人数相当。迫切需要开发针对超级细菌的新疗法，天然存在的抗菌肽是多年来保留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）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。 APD 工具促进了抗菌肽领域的研究和教育，并为该项目奠定了坚实的基础。根据我们的初步结果，我们发现可以从 APD 中提取最关键的参数作为基础。设计和优化有效的抗菌肽，对细菌膜造成损伤，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）确定决定效力的关键参数。基于 APD 的抗菌肽及其模拟物；（2）阐明抗菌肽中决定作用机制和潜在细菌反应基因的关键调节剂；以及（3）检查数据库设计的肽及其模拟物的功效；为了实现这些目标，PI 组建了一个强大的团队，提供了解宿主与病原体在遗传、蛋白质和结构水平上相互作用所需的补充专业知识。以及使用动物模型进行体内肽介导的免疫反应，因为我们的数据库设计的化合物代表了一种新颖的抗菌策略，可以在体外和体内有效地减弱耐药性超级细菌，因此这项创新研究的成果在提供有效的抗菌剂方面具有巨大的潜力。使患者受益的药剂。