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crobial peptides are very toxic for mammalian cells (e.g., bee venom melittin), whereas others show little or no acute cytotoxicity. However, more subtle toxicities have not been studied, although we assume, based on the presence of natural peptides in vivo at concentrations of, e.g., 44 µg/ml in the saliva of an individual with peritonitis, that they can be tolerated at high levels. Another issue would be their lability to proteases in the body. In this regard, there are strategies for protecting the peptides from proteases, including liposomal incorporation or chemical modification.

With this in mind, two very promising clinical trials are underway. The protegrin derivative IB-367 (Intrabiotics, Mountain View, CA) is being examined for its potential against oral mucosaitis, a polymicrobial ulcerative disease of cancer patients. The peptide MBI-226 (Micrologix Biotech, Vancouver) is being investigated for sterilizing catheter insertion sites, thus preventing serious infections caused by colonization of such catheters by skin bacteria. Results from clinical trials to date have indicated efficacy, and MBI-226 has been given fast-track status by the Federal Drug Administration.

Thus cationic antimicrobial peptides are not only important components of the innate defenses of all animals against infections, but synthetic variants thereof hold great potential as a weapon against antibiotic-resistant bacteria. The great sequence and structural diversity offered by peptides (i.e., 20 possible amino acids in each position) will provide many possibilities for drug design.

We thank the many collaborators and laboratory personal who contributed to this work, but particularly Carrie Rosenberger, Brett Finlay, and Mike Gold, who are collaborating on transcriptional array experiments, and Hong Yan and Don Woods, who are performing the animal model infections experiments. Our peptide work is supported by the Canadian Bacterial Diseases Network and the Canadian Cystic Fibrosis Foundations SPARX program. Robert Hancock is the recipient of a Medical Research Council (MRC) of Canada Distinguished Scientist Award, and Monisha Scott has an MRC Scholarship.

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