Mimicry of Host-Defense Peptides by Unnatural Oligomers: Antimicrobial β-Peptides

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Abstract
We have designed β-amino acid oligomers that are helical, cationic, and amphiphilic with the intention of mimicking the biological activity of amphiphilic, cationic α-helical antimicrobial peptides found in nature (e.g., magainins). We have previously identified a 17-residue β-peptide (called β-17) with antibiotic activity similar to that of a magainin derivative against four bacterial species, including two clinical isolates that are resistant to common antibiotics. This β-peptide displays very low hemolytic activity against human red blood cells, which indicates selectivity for bacterial cells over mammalian cells. Here we examine some of the factors important for activity in this class of β-peptides. An amphiphilic helix is necessary, because a nonamphiphilic isomer proved to be inactive. The ratio of cationic to hydrophobic residues is also important. Active β-peptides induce the leakage of β-galactosidase from treated Bacillus subtilis cells, as do α-helical antibiotic peptides, and this similarity suggests that the β-peptide mode of action involves disruption of microbial membranes. This class of β-peptides is not degraded by proteases, which bodes well for biological applications.