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.