Effectively killing pathogenic bacteria is key for the treatment of sepsis. Although various anti-infective drugs have been used for the treatment of sepsis, the therapeutic effect is largely limited by the lack of a specific bacterium-targeting delivery system. This study aimed to develop antibacterial peptides that specifically target pathogenic bacteria for the treatment of sepsis. The lethal bacterial strain Escherichia coli MSI001 was isolated from mice of a cecal ligation and puncture (CLP) model and was used as a target to screen bacterial binding heptapeptides through an integrative bioinformatics approach based on phage display technology and high-throughput sequencing (HTS). Heptapeptides binding to E. coli MSI001 with high affinity were acquired after normalization by the heptapeptide frequency of the library. A representative heptapeptide VTKLGSL (VTK) was selected for fusion with the antibacterial peptide LL-37 to construct the specific-targeting antibacterial peptide VTK-LL37. We found that, in comparison with LL37, VTK-LL37 showed prominent bacteriostatic activity and an inhibitive effect on biofilm formation in vitro. In vivo experiments demonstrated that VTK-LL37 significantly inhibited bacterial growth, reduced HMGB1 expression, alleviated lesions of vital organs and improved the survival of mice subjected to CLP modeling. Furthermore, membrane DEGP and DEGQ were identified as VTK-binding proteins by proteomic methods. This study provides a novel strategy for targeted pathogen killing, which is helpful for the treatment of sepsis in the era of precise medicine.

有效杀灭病原菌是脓毒症治疗的关键。尽管各种抗感染药物已用于治疗脓毒症，但由于缺乏特定的细菌靶向递送系统，治疗效果在很大程度上受到限制。本研究旨在开发专门针对病原菌的抗菌肽，用于治疗败血症。从盲肠结扎和穿刺 (CLP) 模型的小鼠中分离出致死菌株大肠杆菌 MSI001，并通过基于噬菌体展示技术和高通量测序 (HTS) 的综合生物信息学方法作为靶标筛选细菌结合七肽。 . 七肽与大肠杆菌MSI001结合通过文库的七肽频率标准化后获得了高亲和力。选择具有代表性的七肽VTKLGSL（VTK）与抗菌肽LL-37融合，构建特异性靶向抗菌肽VTK-LL37。我们发现，与 LL37 相比，VTK-LL37 在体外显示出显着的抑菌活性和对生物膜形成的抑制作用。体内实验表明，VTK-LL37 显着抑制细菌生长，降低 HMGB1 表达，减轻重要器官损伤，提高接受 CLP 建模的小鼠的存活率。此外，通过蛋白质组学方法将膜 DEGP 和 DEGQ 鉴定为 VTK 结合蛋白。该研究为靶向杀灭病原体提供了一种新策略，