The TFPI-2 derived peptide EDC34 improves outcome of gram-negative sepsis

PLoS Pathog. 2013;9(12):e1003803. doi: 10.1371/journal.ppat.1003803. Epub 2013 Dec 5.

Abstract

Sepsis is characterized by a dysregulated host-pathogen response, leading to high cytokine levels, excessive coagulation and failure to eradicate invasive bacteria. Novel therapeutic strategies that address crucial pathogenetic steps during infection are urgently needed. Here, we describe novel bioactive roles and therapeutic anti-infective potential of the peptide EDC34, derived from the C-terminus of tissue factor pathway inhibitor-2 (TFPI-2). This peptide exerted direct bactericidal effects and boosted activation of the classical complement pathway including formation of antimicrobial C3a, but inhibited bacteria-induced activation of the contact system. Correspondingly, in mouse models of severe Escherichia coli and Pseudomonas aeruginosa infection, treatment with EDC34 reduced bacterial levels and lung damage. In combination with the antibiotic ceftazidime, the peptide significantly prolonged survival and reduced mortality in mice. The peptide's boosting effect on bacterial clearance paired with its inhibiting effect on excessive coagulation makes it a promising therapeutic candidate for invasive Gram-negative infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use*
  • Drug Evaluation, Preclinical
  • Escherichia coli Infections / drug therapy
  • Glycoproteins / chemistry
  • Glycoproteins / pharmacology
  • Glycoproteins / therapeutic use*
  • Gram-Negative Bacterial Infections / drug therapy*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Peptide Fragments / pharmacology
  • Peptide Fragments / therapeutic use*
  • Pseudomonas Infections / drug therapy
  • Pseudomonas aeruginosa / drug effects
  • Pseudomonas aeruginosa / growth & development
  • Sepsis / drug therapy*
  • Treatment Outcome

Substances

  • Anti-Bacterial Agents
  • EDC34 peptide
  • Glycoproteins
  • Peptide Fragments
  • tissue-factor-pathway inhibitor 2

Grant support

This work was supported by grants from the Swedish Research Council (projects 521-2009-3378), the Welander-Finsen, Crafoord, Österlund, Knut and Alice Wallenberg, and Kock Foundations, XImmune AB, The Royal Physiographic Society in Lund, and The Swedish Government Funds for Clinical Research (ALF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.