Investigation of capsule interactions that promote antimicrobial peptide activity

项目摘要。 肺炎克雷伯菌胞外多糖胶囊对抗菌药物的穿透作用 保护细菌免受先天免疫系统的侵害。而胶囊则抑制大多数寄主防御肽和 多粘菌素抗生素是几种两亲性抗菌肽，已被鉴定为对 被囊化的肺炎克雷伯菌。然而，目前尚不清楚是什么使一些多肽能够避免被K。 肺炎胶囊，而它有效地中和了大多数其他的。我们已经发现了一种机制，可以让 合成抗菌肽以克服胶囊抑制。不活跃状态下特定氨基酸的变化 序列使多肽能够结合、聚集和破坏被囊层，使肺炎克雷伯菌容易感染 它们的膜攻击。通过这项提议，我们将1)探索这种先天免疫宿主的新机制 杀灭被包裹的肺炎克雷伯菌的防御肽，以及2)氨基酸序列和位置的特征 促进对被包裹细菌的活性的变异。我们的结果将为我们提供重要的见解 肺炎克雷伯菌和其他被包裹的细菌的免疫逃避，以及确定机制原理将有助于 开发新的治疗方法，以克服胶囊障碍。

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.