PepSAVI-MS for discovery of novel botanical antimicrobial peptides

PepSAVI-MS 用于发现新型植物抗菌肽

• 批准号: 10350568
• 负责人: Leslie M. Hicks
• 金额: $ 25.81万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350568
• 关键词: Address; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteria; Bacterial Infections; Biological; Biological Assay; Biological Products; Biological Testing; Botanicals; Breathing; Characteristics; Chemicals; Chemistry; Clinical; Colistin; Community Hospitals; Coupled; Detection; Developing Countries; Drug Kinetics; Drug resistance; ESKAPE pathogens; Effectiveness; Enterobacteriaceae Infections; Environment; Evolution; Future; Goals; Heel; Hybrids; Informatics; Laboratories; Lead; Length; Libraries; Life; Mass Spectrum Analysis; Medicine; Metabolic; Methods; Microbe; Mining; Modernization; Modification; Molecular; Multi-Drug Resistance; Natural Products; Nature; Nosocomial Infections; Organism; Penetration; Peptides; Pharmaceutical Preparations; Pharmacology; Phenotype; Plant Extracts; Plants; Population; Post-Translational Protein Processing; Primary Health Care; Property; Proteins; Proteomics; Resources; Ribosomes; Savings; Signal Transduction; Soil; Source; Specificity; Statistical Models; Streptomycin; Techniques; Testing; Therapeutic; Tissues; Validation; Work; antimicrobial; antimicrobial drug; antimicrobial peptide; base; carbapenem-resistant Enterobacteriaceae; data handling; drug discovery; experimental study; falls; genome sequencing; immunogenicity; improved; infectious disease treatment; innovative technologies; instrumentation; knowledge base; lens; microbial; microorganism; novel; novel therapeutics; peptidomimetics; relative cost; scaffold; screening; small molecule therapeutics; therapy development

ABSTRACT The continued evolution of antimicrobial resistance emphasizes the dire need for discovery of antibiotic therapeutics with novel mechanisms of action. Technological advances in genome sequencing, drug library creation, and structural informatics have not advanced infectious disease treatments sufficiently. While natural products have long served as inspiration for novel therapeutic scaffolds, we posit peptide-derived entities offer great potential to address current needs due to their unique mechanisms of action, penetration and selectively. Herein, we describe our PepSAVI-MS pipeline to discover and characterize peptides with antimicrobial activity through implementation of a hybrid bioassay-guided/peptidomics platform. We directly identify botanical peptides contributing to bioactivity profiles using robust microbial bioassays optimized for peptide screening and using a mass spectrometry-based peptidomics approach coupled to statistical modeling and informatics to identify and further characterize these peptides at the molecular level. These potential lead compounds are then tested against an extensive panel of clinical ESKAPE pathogens, as well as for favorable drug characteristics and determination of mechanism-of-action. Our platform enables robust mining of plants and other natural sources for peptidyl species with unique or broad-spectrum anti-infective properties and has the potential to lead to the discovery of novel chemistries at the forefront of modern drug discovery.

摘要 抗生素耐药性的持续演变强调了发现抗生素的迫切需要 具有新的作用机制的治疗剂。基因组测序、药物文库的技术进展 创造和结构信息学并没有充分推进传染病的治疗。而天然 产品长期以来一直是新型治疗支架的灵感来源，我们开发的肽衍生实体提供 由于其独特的作用机制、渗透性和选择性，在满足当前需求方面具有巨大潜力。 在此，我们描述了我们的PepSAVI-MS管道，以发现和表征具有抗微生物活性的肽 通过实施混合生物测定指导/肽组学平台。我们可以直接识别植物 使用针对肽筛选优化的稳健微生物生物测定法对生物活性谱有贡献的肽 并使用基于质谱的肽组学方法结合统计建模和信息学， 在分子水平上鉴定并进一步表征这些肽。这些潜在的先导化合物是 然后针对广泛的临床ESKAPE病原体以及有利的药物进行测试， 特征和作用机制的测定。我们的平台能够对植物进行稳健的开采， 具有独特或广谱抗感染特性的肽基物质的其它天然来源， 有可能导致在现代药物发现的最前沿发现新的化学物质。