title: Hydrocarbon-stapled lipopeptides exhibit selective antimicrobial activity.
abstract: Antimicrobial peptides (AMPs) occur widely in nature and have been studied for their therapeutic potential. AMPs are of interest due to the large number of possible chemical structural combinations using natural and unnatural amino acids, with varying effects on their biological activities. Using physicochemical properties from known naturally occurring amphipathic cationic AMPs, several hydrocarbon-stapled lipopeptides (HSLPs) were designed, synthesized, and tested for antimicrobial properties. Peptides were chemically modified by N-terminal acylation, C-terminal amidation, and some were hydrocarbon stapled by intramolecular olefin metathesis. The effects of peptide length, amphipathic character, and stapling on antimicrobial activity were tested against Escherichia coli, three species of Gram-positive bacteria (Staphylococcus aureus, Bacillus megaterium, and Enterococcus faecalis), and two strains of Candida albicans. Peptides were shown to disrupt liposomes of different phospholipid composition, as measured by leakage of a fluorescent compound from vesicles. Peptides with (S)-2-(4'-pentenyl)-alanine substituted for l-alanine in a reference peptide showed a marked increase in antimicrobial activity, hemolysis, and membrane disruption. Stapled peptides exhibited slightly higher antimicrobial potency; those with greatest hydrophobic character showed the greatest hemolysis and liposome leakage, but lower antimicrobial activity. The results support a model of HSLPs as membrane-disruptive AMPs with potent antimicrobial activity and relatively low hemolytic potential at biologically active peptide concentrations.
authors.affiliation: Department of Chemistry and Biochemistry, Southwestern University, Georgetown, Texas, 78626.|Department of Microbiology, McGovern Medical School, formerly The University of Texas Health Science Center at Houston (UTHealth) Medical School, Texas, 77030.
authors.forename: Zachary B
authors.initials: ZB
authors.lastname: Jenner
authors.affiliation: Department of Chemistry, University of Texas, Austin, Texas, 78712.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Crittenden
authors.affiliation: Department of Biology, Southwestern University, Georgetown, Texas, 78626.
authors.forename: Martín
authors.initials: M
authors.lastname: Gonzalez
authors.affiliation: Department of Chemistry, University of Texas, Austin, Texas, 78712.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Brodbelt
authors.affiliation: Department of Chemistry and Biochemistry, Southwestern University, Georgetown, Texas, 78626.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Bruns
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001410:Bacillus megaterium / Q000187:drug effects / Q000472:pathogenicity; D002176:Candida albicans / Q000187:drug effects / Q000472:pathogenicity; D013293:Enterococcus faecalis / Q000187:drug effects / Q000472:pathogenicity; D004912:Erythrocytes / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000472:pathogenicity; D006461:Hemolysis; D006801:Humans; D006838:Hydrocarbons / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055666:Lipopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008081:Liposomes; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D006838:Hydrocarbons; D055666:Lipopeptides; D008081:Liposomes
keywords: antimicrobial peptide; hydrocarbon staple; lipopeptide; membrane disruption; ring-closing metathesis