title: Fragmented tissue factor pathway inhibitor (TFPI) and TFPI C-terminal peptides eliminate serum-resistant Escherichia coli from blood cultures.
abstract: BACKGROUND
  Tissue factor pathway inhibitor (TFPI) is a major regulator of blood clotting. Receipt of recombinant TFPI (rTFPI) protected animals from death in Escherichia coli-induced severe sepsis models and is under evaluation in a phase III clinical trial involving patients with severe community-acquired pneumonia. Because the mechanism of action of rTFPI in acute bacterial infection is not well understood, we sought to identify and map rTFPI peptides that have antimicrobial activity against E. coli.
  
  
  METHODS
  Fragmented rTFPI and C-terminal TFPI peptide activities against pathogenic E. coli strains were measured in ex vivo blood cultures and in serum.
  
  
  RESULTS
  The C-terminal peptides exhibited complement-dependent antibacterial activity and directly interacted with the bacterial cell surface of E. coli. Both complement-mediated killing and cell-surface binding were reversed by low amounts of heparin.
  
  
  CONCLUSIONS
  Our investigation revealed a previously unidentified mechanism of antibacterial activity for TFPI. C-terminal rTFPI fragments kill serum-resistant E. coli though the complement pathway of the innate immune system, suggesting a multimodal mechanism of action of rTFPI that may assist in reducing mortality in animal models of severe sepsis and contribute to therapeutic effectiveness.
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, California 94608, USA.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schirm
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.forename: Lori L
authors.initials: LL
authors.lastname: Jennings
authors.forename: Paul
authors.initials: P
authors.lastname: Jedrzejewski
authors.forename: Yumin
authors.initials: Y
authors.lastname: Dai
authors.forename: Stephen
authors.initials: S
authors.lastname: Hardy
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001769:Blood / Q000382:microbiology; D003171:Complement Pathway, Classical; D004926:Escherichia coli / Q000187:drug effects*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D008074:Lipoproteins; D010446:Peptide Fragments; C051928:lipoprotein-associated coagulation inhibitor; D006493:Heparin; D010447:Peptide Hydrolases