Improvement of Therapeutic Index by the Combination of Enhanced Peptide Cationicity and Proline Introduction

Antimicrobial peptides (AMPs) are promising candidates for new therapeutics to combat the emergence of an increasing number of multidrug-resistant pathogens. However, a major obstacle to the systemic application of AMPs is their possible toxicity. In this study, we improved the therapeutic index of the typical AMP F5W-magainin 2 by simultaneously introducing positive charges (+9–+10) and Pro residues. The former and latter contributed to enhanced antimicrobial activity and reduced cytotoxicity, respectively. The results were sensitive to the positions of Pro substitution. The antimicrobial mechanism was considered to involve both membrane permeabilization and DNA binding. The latter was affected by the peptide charge but not the presence of Pro. The neutralization of lipopolysaccharides, another important role of AMPs, was not very sensitive to either the peptide charge or Pro introduction. This strategy using intrinsic amino acids is also promising from the viewpoints of the economic mass production of AMPs and safety of metabolized peptides.