PepSAVI-MS for discovery of novel botanical antimicrobial peptides

摘要 抗菌素耐药性的持续演变强调迫切需要发现 具有新颖作用机制的抗生素疗法。基因组技术进步 测序、药物库创建和结构信息学并未促进传染病的发展 治疗充分。虽然天然产品长期以来一直是小说的灵感来源 治疗支架，我们认为肽衍生实体为解决当前的问题提供了巨大的潜力 由于其作用机制独特、渗透力强、选择性强。在此，我们描述 我们的 PepSAVI-MS 管道通过以下方式发现和表征具有抗菌活性的肽 实施混合生物测定引导/肽组学平台。我们直接鉴定植物 使用针对肽优化的强大微生物生物测定法对生物活性谱做出贡献 筛选和使用基于质谱的肽组学方法与统计相结合 建模和信息学以在分子水平上识别和进一步表征这些肽。 然后针对广泛的临床 ESKAPE 小组对这些潜在的先导化合物进行测试 病原体，以及有利的药物特性和机制的确定 行动。我们的平台能够对植物和其他天然来源进行肽基物种的稳健挖掘 具有独特或广谱抗感染特性，并有可能导致 处于现代药物发现前沿的新型化学物质的发现。

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.