Database designed novel anti-MRSA peptides

数据库设计的新型抗 MRSA 肽

• 批准号: 9174841
• 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/9174841
• 关键词: AIDS/HIV problem; Acinetobacter; Amino Acid Sequence; Animal Model; Antibiotics; Antimalarials; Apoptosis; Attenuated; Bacterial DNA; Biological; Biology; Biophysics; Catheters; Cations; Cessation of life; Classification; DNA Microarray Chip; Dangerousness; Data; Databases; Education; Elements; Engineering; Enterobacter; Enterococcus faecium; Evaluation; Evolution; Frequencies; Future; Generations; Genes; Genetic; Healthcare; Host Defense; Hydrophobicity; Immune response; In Vitro; Infection; Invaded; Investigation; Klebsiella pneumonia bacterium; Laboratories; Life; Mediating; Medical center; Membrane; Microbial Biofilms; Modeling; Molecular; Mus; Names; Natural Immunity; Nebraska; Outcome; Patients; Peptides; Positioning Attribute; Prevention; Property; Proteins; Pseudomonas aeruginosa; Research; Resistance; Resources; Scientist; Solid; Source; Staphylococcus aureus; Statistical Data Interpretation; Structure; Superbug; Surface; System; Testing; United States; Universities; Update; Virulence Factors; antimicrobial; antimicrobial drug; antimicrobial peptide; base; combat; database design; design; immunoregulation; in vivo; innovation; killings; membrane model; methicillin resistant Staphylococcus aureus; microbial; mortality; natural antimicrobial; novel; pathogen; peptidomimetics; 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（由申请方提供）：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，由于其能够逃避传统抗生素的杀灭，因此是危及生命的超级细菌。根据疾病控制和预防中心的数据，这六种类型的有害微生物造成了三分之二的医疗相关感染，导致美国每年99，000人死亡。令人震惊的是，每年死于耐甲氧西林金黄色葡萄球菌（MRSA）的人数与艾滋病毒/艾滋病造成的人数相当。因此，迫切需要开发针对超级细菌的新疗法。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）。这一综合数据库便于命名、分类、统计分析、检索、预测和设计 具有所需性能的新型抗菌剂。APD工具促进了抗菌肽领域的研究和教育，为本项目奠定了坚实的基础。基于我们的初步结果，我们假设，最关键的参数可以提取的APD作为基础，设计和优化强效的抗菌肽，造成细菌膜上的损害，导致细菌死亡和增强宿主防御。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的抗菌肽及其模拟物的效力的关键参数：（2）阐明抗菌肽中决定作用机制和潜在细菌应答基因的关键调节剂;和（3）检测数据库设计的肽及其模拟物在体内抗细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。由于我们的数据库设计的化合物代表了一种新的抗菌策略，可以有效地在体外和体内减弱耐药性超级细菌，因此这项创新研究的结果在提供有益于患者的强效抗菌剂方面具有巨大潜力。