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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.

Original publication

DOI

10.1074/jbc.M113.459560

Type

Journal article

Journal

J Biol Chem

Publication Date

12/07/2013

Volume

288

Pages

20162 - 20172

Keywords

Antimicrobial Peptides, Membrane Biophysics, Microscopy, Molecular Dynamics, Nuclear Magnetic Resonance, Protein Design, Protein Folding, Antimicrobial Cationic Peptides, Cathelicidins, Cecropins, Circular Dichroism, Dose-Response Relationship, Drug, Hemolysis, Humans, Magainins, Microbial Sensitivity Tests, Models, Molecular, Molecular Dynamics Simulation, Peptides, Protein Binding, Protein Folding, Protein Multimerization, Protein Structure, Secondary, Spectroscopy, Fourier Transform Infrared