Cationic antimicrobial peptides contain a number of arginine residues. On one hand the high arginine content renders the production costs well above those of other natural peptides. On the other, the physical attributes that make arginine derivatives expensive (extended hydrophobic side chain capped with the most positively charged guanidinium group) equips arginine-rich peptides with strong cell and tissue penetrating abilities. Indeed, arginine supplementation has been shown to enhance wound healing and collagen deposition in rodents and humans.
Host defense peptides are preferably administered as topical therapeutic agents. We have investigated whether the designer proline-arginine-rich peptide dimer, A3-APO can enter the circulation when applied to the ear skin of mice. Efficacy of peptide monotherapy as a transdermal administration option was assessed in a systemic mouse Acinetobacter baumannii model. A3-APO reduced mortality and demonstrated a statistically significant reduction of blood bacterial counts. The single-chain peptidic metabolite of A3-APO was efficacious when applied to the ear or tail. Based on the blood bacterial counts, Chex1-Arg20 treatment was successful albeit to a decreasing extent as the skin thickness grows.
Our current studies indicate that the skin layer does not need to be compromised for host defense peptide transport. The highest efficacy, similar to those with intramuscular peptide administration, was obtained with pre-infection peptide application to intact ear. This confirms earlier studies suggesting that activation of cellular mechanisms in innate activity, rather than direct killing of bacteria, is the predominant antimicrobial action of cationic antimicrobial peptides. These studies highlight the potential of A3-APO analogs in human therapy when administered transdermally, although the thickness of the skin plays a major role in peptide efficacy. Additional animal studies, preferably with pigs whose skin is more similar to that of humans, are needed to characterize the scope and limitations of the approach.