PepSAVI-MS for discovery of novel botanical antimicrobial peptides

摘要 抗菌素耐药性的持续演变强调了发现细菌的迫切需要 具有新作用机制的抗生素疗法。基因组技术的进步 测序、药库创建和结构信息学并没有使传染病变得更先进 足够的治疗。虽然天然产品长期以来一直是小说的灵感来源 治疗支架，我们假设多肽衍生实体提供了巨大的潜力来解决目前 需求由于其独特的作用机制、渗透性和选择性。在此，我们描述了 我们的PepSAVI-MS流水线通过以下途径发现和表征具有抗菌活性的多肽 实施混合生物测定指导/多肽分析平台。我们直接识别植物学 利用针对多肽进行优化的强健微生物生物测定，对多肽的生物活性作出贡献 筛选和使用基于质谱学的多肽组学方法与统计学相结合 建模和信息学，以在分子水平上识别和进一步表征这些多肽。 然后，将这些潜在的先导化合物与广泛的临床ESKAPE小组进行测试 病原体，以及有利的药物特性和作用机制的测定。 行动。我们的平台支持对植物和其他自然来源的多肽物种进行强有力的挖掘 具有独特或广谱的抗感染特性，并有可能导致 在现代药物发现的前沿发现新的化学物质。

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.