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 sp...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 VTKbinding 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.展开更多
基金supported by grants from the NSFC-Guangdong Joint Foundation of China(U1601225)the National Natural Science Foundation of China(81671965 and 82130063)+1 种基金Special Support Plan for Outstanding Talents of Guangdong Province(2019JC05Y340)Guangdong Provincial Science and Technology Project(2016A020216015).
文摘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 VTKbinding 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.
