Triggering innate immunity

VANCOUVER—The growing resistance of many microbes to antibiotics is forcing companies to explore other avenues of anti-infective therapeutics development. Recently, researchers at Inimex Pharmaceuticals and the University of British Columbia described their efforts to develop therapeutic peptides that selectively modulate the innate immune response against a variety of microbes.

As they described in Nature Biotechnology, the researchers screened a library of small cationic peptides for immunomodulatory activity and selected a 13-mer—IDR-1—for further analysis. They tested the peptide in a mouse model of aggressive bacterial infection with S. aureus. They found that although the peptide could not eradicate the bacteria completely, it significantly decreased bacterial counts and prevented mortality, whether given before or shortly after infection. The researchers found that IDR-1 was also efficacious against S. enterica serovar Typhimurium, MRSA, and VRE.

They then tested the peptide in bacterial culture and found that it did not have direct antimicrobial activity, suggesting it worked through another pathway in the host. Using microarrays, the researchers analyzed the effect of IDR-1 on human monocytes and found that it upregulated proteins involved in the MAP kinase pathway, as well as numerous cytokines and chemokines. Furthermore, specific inhibitors of pathways involved in innate immunity blocked IDR-1-mediated gene induction.

"Given the prophylactic efficacy of IDR-1, and its inability to engender resistance, appropriate uses for such agents would include situations in which there is a high risk of infection such as in ventilator-associated pneumonia, after major surgeries, catheterization or insertion of other medical devices, and high-dose myelosuppressive chemotherapy," write the researchers.