Investigation of capsule interactions that promote antimicrobial peptide activity

项目摘要。 肺炎克雷伯氏菌的胞外多糖荚膜抵抗抗微生物剂的渗透， 保护细菌免受先天免疫系统的侵害。而胶囊抑制大多数宿主防御肽， 除了多粘菌素抗生素之外，已经鉴定了一些两亲性抗微生物肽，其保留了抗多粘菌素抗生素的活性。 囊状K.肺炎。然而，尚不清楚是什么使某些肽能够避免被K. pneumoniae胶囊，而它有效地中和大多数其他。我们发现了一种机制 合成抗微生物肽以克服胶囊抑制。非活性蛋白中的特定氨基酸变化 序列使肽能够结合、聚集和破坏胶囊层，留下K。极易受到 膜攻击。通过本研究，我们将：1）在天然免疫宿主中探索这一新机制 防御肽杀死被包囊的K.肺炎，和2）表征氨基酸序列和位置 这些变异促进了对胶囊化细菌的活性。我们的研究结果将提供重要的见解， 免疫逃避K.肺炎和其他被囊化的细菌，并确定机械原理将有助于 开发新的治疗方法来克服胶囊屏障。

Project Summary. The extracellular polysaccharide capsule of Klebsiella pneumoniae resists penetration by antimicrobials and protects the bacteria from the innate immune system. While capsule inhibits most host defense peptides and polymyxin antibiotics, a few amphipathic antimicrobial peptides have been identified that retain activity against capsulated K. pneumoniae. However, it is not known what enables some peptides to avoid sequestration by K. pneumoniae capsule while it effectively neutralizes most others. We have uncovered a mechanism that allows synthetic antimicrobial peptides to overcome capsule inhibition. Specific amino acid changes in inactive sequences enable peptides to bind, aggregate, and disrupt capsule layers, leaving K. peumoniae vulnerable to their membrane attack. Through this proposal we will 1) explore this new mechanism in innate immune host defense peptides that kill capsulated K. pneumoniae, and 2) characterize amino acid sequence and positional variations that promote activity towards capsulated bacteria. Our results will provide important insight into immune evasion by K. pneumoniae and other capsulated bacteria, and identify mechanistic principles will aid the development new therapeutic approaches to overcome the capsule barrier.