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（由适用提供）：Eskape病原体，包括粪肠球菌，金黄色葡萄球菌，Klebsiella肺炎，Baumanii，baumanii，pseudomonas aeruginosa和肠道物种，由于他们的能力逃脱了杀害的能力，因此逃脱了生命的超级烟草。根据疾病控制和预防中心的说法，这六种错误的错误导致三分之二的医疗保健相关感染，每年在美国每年99,000人死亡。令人惊讶的是，耐甲氧西林的金黄色葡萄球菌（MRSA）每年的死亡频率与艾滋病毒/艾滋病引起的死亡频率相当。因此，迫切需要开发针对超级细菌的新疗法。天然发生的抗菌胡椒体是多年来一直保持效力的普遍防御分子。为了有效地探索这些有趣的化合物，我们一直在构建，扩展和更新广泛使用的抗微生物肽数据库（APD; http; http://aps.unmc.edu/ap）。这种全面的数据库设施是命名，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工具已经准备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。基于我们的初步结果，我们假设可以从APD中提取大多数关键参数，作为设计和优化潜在的抗菌胡椒的基础，从而造成细菌中位数损害，从而导致细菌死亡并增强宿主防御。为了检验我们的假设，我们设计了以下特定目的：（1）确定确定抗微生物肽效力及其基于APD的模仿的关键参数； （2）阐明抗菌肽中的临界调节剂，以决定作用机理和潜在的细菌反应基因； （3）检查数据库设计的肽及其对体内细菌生物膜感染的模仿和免疫调节机制的有效性。为了实现这些目标，PI组装了一个强大的团队，该团队提供了所需的完整专业知识，以了解遗传，蛋白质和结构水平上的宿主 - 病原体相互作用，以及使用动物模型在体内肽介导的免疫调查。由于我们的数据库设计的化合物代表了一种新型的抗菌策略，该抗菌策略有效地减弱了体外和体内的耐药性超级细菌，因此这项创新研究的结果具有巨大的潜力，可以使有效的抗菌药物受益于患者。