title: Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes.
abstract: Antimicrobial peptides or their synthetic mimics are a promising class of potential new antibiotics. Herein we assess the effect of the type of cationic side chain (i.e., guanidino vs. amino groups) on the membrane perturbing mechanism of antimicrobial α-peptide-β-peptoid chimeras. Langmuir monolayers composed of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol (DPPG) were used to model cytoplasmic membranes of both Gram-positive and Gram-negative bacteria, while lipopolysaccharide Kdo2-lipid A monolayers were mimicking the outer membrane of Gram-negative species. We report the results of the measurements using an array of techniques, including high-resolution synchrotron surface X-ray scattering, epifluorescence microscopy, and in vitro antimicrobial activity to study the molecular mechanisms of peptidomimetic interaction with bacterial membranes. We found guanidino group-containing chimeras to exhibit greater disruptive activity on DPPG monolayers than the amino group-containing analogues. However, this effect was not observed for lipopolysaccharide monolayers where the difference was negligible. Furthermore, the addition of the nitrobenzoxadiazole fluorophore did not reduce the insertion activity of these antimicrobials into both model membrane systems examined, which may be useful for future cellular localization studies.
authors.affiliation: Center for Molecular Study of Condensed Soft Matter (μCoSM), Pritzker Institute of Biomedical Science and Engineering and Department of Physics, Illinois Institute of Technology, 3440 S. Dearborn St., Chicago, IL 60616 (USA).
authors.forename: Konstantin
authors.initials: K
authors.lastname: Andreev
authors.affiliation: Center for Molecular Study of Condensed Soft Matter (μCoSM), Pritzker Institute of Biomedical Science and Engineering and Department of Physics, Illinois Institute of Technology, 3440 S. Dearborn St., Chicago, IL 60616 (USA).
authors.forename: Christopher
authors.initials: C
authors.lastname: Bianchi
authors.affiliation: Department of Chemistry, Technical University of Denmark, Kemitorvet 207, DK-2800 Kgs. Lyngby (Denmark).
authors.forename: Jonas S
authors.initials: JS
authors.lastname: Laursen
authors.affiliation: Department of Systems Biology, Technical University of Denmark, Matematiktorvet 301, DK-2800 Kgs. Lyngby (Denmark).
authors.forename: Linda
authors.initials: L
authors.lastname: Citterio
authors.affiliation: , National Food Institute, Technical University of Denmark, Søltofts Plads 221, DK-2800, Kgs Lyngby (Denmark).
authors.forename: Line
authors.initials: L
authors.lastname: Hein-Kristensen
authors.affiliation: Department of Systems Biology, Technical University of Denmark, Matematiktorvet 301, DK-2800 Kgs. Lyngby (Denmark).
authors.forename: Lone
authors.initials: L
authors.lastname: Gram
authors.affiliation: Advanced Photon Source, Argonne National Laboratory, 9700 S. Cass Ave., Lemont, IL 60439 (USA).
authors.forename: Ivan
authors.initials: I
authors.lastname: Kuzmenko
authors.affiliation: Department of Chemistry, Technical University of Denmark, Kemitorvet 207, DK-2800 Kgs. Lyngby (Denmark).
authors.forename: Christian A
authors.initials: CA
authors.lastname: Olsen
authors.affiliation: Center for Molecular Study of Condensed Soft Matter (μCoSM), Pritzker Institute of Biomedical Science and Engineering and Department of Physics, Illinois Institute of Technology, 3440 S. Dearborn St., Chicago, IL 60616 (USA).
authors.forename: David
authors.initials: D
authors.lastname: Gidalevitz
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology; D001419:Bacteria / Q000737:chemistry* / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism; D019791:Guanidine / Q000737:chemistry* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology; D010715:Phosphatidylglycerols / Q000737:chemistry / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; C506188:Kdo2-lipid A; D008070:Lipopolysaccharides; D057786:Peptidomimetics; D010715:Phosphatidylglycerols; D019791:Guanidine; C030345:1,2-dipalmitoylphosphatidylglycerol
keywords: Antimicrobial peptidomimetics; Bacterial membrane; Guanidinium cation; Peptide–peptoid chimeras; Phosphatidylglycerol; X-ray scattering