title: Mimicry of host-defense peptides by unnatural oligomers: antimicrobial beta-peptides.
abstract: We have designed beta-amino acid oligomers that are helical, cationic, and amphiphilic with the intention of mimicking the biological activity of amphiphilic, cationic alpha-helical antimicrobial peptides found in nature (e.g., magainins). We have previously identified a 17-residue beta-peptide (called beta-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 beta-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 beta-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 beta-peptides induce the leakage of beta-galactosidase from treated Bacillus subtilis cells, as do alpha-helical antibiotic peptides, and this similarity suggests that the beta-peptide mode of action involves disruption of microbial membranes. This class of beta-peptides is not degraded by proteases, which bodes well for biological applications.
authors.affiliation: Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, USA.
authors.forename: Emilie A
authors.initials: EA
authors.lastname: Porter
authors.forename: Bernard
authors.initials: B
authors.lastname: Weisblum
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Gellman
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects / Q000201:enzymology; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000737:chemistry; D004355:Drug Stability; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism; D016984:Enterococcus faecium / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D054806:Magainins; D008826:Microbial Sensitivity Tests; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D029867:Xenopus Proteins
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D054806:Magainins; D009842:Oligopeptides; D029867:Xenopus Proteins; D003515:Cycloleucine; C053301:magainin 2 peptide, Xenopus; C065594:cispentacin; D010450:Endopeptidases