title: Synthetic cationic peptide IDR-1002 provides protection against bacterial infections through chemokine induction and enhanced leukocyte recruitment.
abstract: With the rapid rise in the incidence of multidrug resistant infections, there is substantial interest in host defense peptides as templates for production of new antimicrobial therapeutics. Natural peptides are multifunctional mediators of the innate immune response, with some direct antimicrobial activity and diverse immunomodulatory properties. We have previously developed an innate defense regulator (IDR) 1, with protective activity against bacterial infection mediated entirely through its effects on the immunity of the host, as a novel approach to anti-infective therapy. In this study, an immunomodulatory peptide IDR-1002 was selected from a library of bactenecin derivatives based on its substantially more potent ability to induce chemokines in human PBMCs. The enhanced chemokine induction activity of the peptide in vitro correlated with stronger protective activity in vivo in the Staphylococcus aureus-invasive infection model, with a >5-fold reduction in the protective dose in direct comparison with IDR-1. IDR-1002 also afforded protection against the Gram-negative bacterial pathogen Escherichia coli. Chemokine induction by IDR-1002 was found to be mediated through a Gi-coupled receptor and the PI3K, NF-kappaB, and MAPK signaling pathways. The protective activity of the peptide was associated with in vivo augmentation of chemokine production and recruitment of neutrophils and monocytes to the site of infection. These results highlight the importance of the chemokine induction activity of host defense peptides and demonstrate that the optimization of the ex vivo chemokine-induction properties of peptides is a promising method for the rational development of immunomodulatory IDR peptides with enhanced anti-infective activity.
authors.affiliation: Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Nijnik
authors.forename: Laurence
authors.initials: L
authors.lastname: Madera
authors.forename: Shuhua
authors.initials: S
authors.lastname: Ma
authors.forename: Matthew
authors.initials: M
authors.lastname: Waldbrook
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Elliott
authors.forename: Donna M
authors.initials: DM
authors.lastname: Easton
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Mayer
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Mullaly
authors.forename: Jason
authors.initials: J
authors.lastname: Kindrachuk
authors.forename: Håvard
authors.initials: H
authors.lastname: Jenssen
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D001424:Bacterial Infections / Q000378:metabolism* / Q000382:microbiology / Q000517:prevention & control; D002460:Cell Line; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D054410:Chemokine CCL7 / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D013203:Staphylococcal Infections / Q000382:microbiology / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D054360:Chemokine CXCL1; D018925:Chemokines; C549067:IDR 1002; D016209:Interleukin-8; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases