title: Anti-antimicrobial peptides: folding-mediated host defense antagonists.
abstract: Antimicrobial or host defense peptides are innate immune regulators found in all multicellular organisms. Many of them fold into membrane-bound α-helices and function by causing cell wall disruption in microorganisms. Herein we probe the possibility and functional implications of antimicrobial antagonism mediated by complementary coiled-coil interactions between antimicrobial peptides and de novo designed antagonists: anti-antimicrobial peptides. Using sequences from native helical families such as cathelicidins, cecropins, and magainins we demonstrate that designed antagonists can co-fold with antimicrobial peptides into functionally inert helical oligomers. The properties and function of the resulting assemblies were studied in solution, membrane environments, and in bacterial culture by a combination of chiroptical and solid-state NMR spectroscopies, microscopy, bioassays, and molecular dynamics simulations. The findings offer a molecular rationale for anti-antimicrobial responses with potential implications for antimicrobial resistance.
authors.affiliation: National Physical Laboratory, Teddington, Middlesex TW11 0WL, United Kingdom.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Ryan
authors.forename: Baptiste
authors.initials: B
authors.lastname: Lamarre
authors.forename: Ting
authors.initials: T
authors.lastname: Diu
authors.forename: Jascindra
authors.initials: J
authors.lastname: Ravi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Judge
authors.forename: Adam
authors.initials: A
authors.lastname: Temple
authors.forename: Matthew
authors.initials: M
authors.lastname: Carr
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cerasoli
authors.forename: Bo
authors.initials: B
authors.lastname: Su
authors.forename: Howard F
authors.initials: HF
authors.lastname: Jenkinson
authors.forename: Glenn
authors.initials: G
authors.lastname: Martyna
authors.forename: Jason
authors.initials: J
authors.lastname: Crain
authors.forename: Anthony
authors.initials: A
authors.lastname: Watts
authors.forename: Maxim G
authors.initials: MG
authors.lastname: Ryadnov
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D054804:Cathelicidins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D054807:Cecropins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D054806:Magainins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D017510:Protein Folding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D054807:Cecropins; D054806:Magainins; D010455:Peptides
keywords: Antimicrobial Peptides; Membrane Biophysics; Microscopy; Molecular Dynamics; Nuclear Magnetic Resonance; Protein Design; Protein Folding