title: Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides.
abstract: Antimicrobial peptides (AMPs) and their mimics are emerging as promising antibiotic agents. We present a library of "ampetoids" (antimicrobial peptoid oligomers) with helical structures and biomimetic sequences, several members of which have low-micromolar antimicrobial activities, similar to cationic AMPs like pexiganan. Broad-spectrum activity against six clinically relevant BSL2 pathogens is also shown. This comprehensive structure-activity relationship study, including circular dichroism spectroscopy, minimum inhibitory concentration assays, hemolysis and mammalian cell toxicity studies, and specular x-ray reflectivity measurements shows that the in vitro activities of ampetoids are strikingly similar to those of AMPs themselves, suggesting a strong mechanistic analogy. The ampetoids' antibacterial activity, coupled with their low cytotoxicity against mammalian cells, make them a promising class of antimicrobials for biomedical applications. Peptoids are biostable, with a protease-resistant N-substituted glycine backbone, and their sequences are highly tunable, because an extensive diversity of side chains can be incorporated via facile solid-phase synthesis. Our findings add to the growing evidence that nonnatural foldamers will emerge as an important class of therapeutics.
authors.affiliation: Department of Chemical and Biological Engineering, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA.
authors.forename: Nathaniel P
authors.initials: NP
authors.lastname: Chongsiriwatana
authors.forename: James A
authors.initials: JA
authors.lastname: Patch
authors.forename: Ann M
authors.initials: AM
authors.lastname: Czyzewski
authors.forename: Michelle T
authors.initials: MT
authors.lastname: Dohm
authors.forename: Andrey
authors.initials: A
authors.lastname: Ivankin
authors.forename: David
authors.initials: D
authors.lastname: Gidalevitz
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Zuckermann
authors.forename: Annelise E
authors.initials: AE
authors.lastname: Barron
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004926:Escherichia coli; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D017356:Synchrotrons
chemical_list: D023181:Antimicrobial Cationic Peptides; D008051:Lipid Bilayers