title: Iterative antimicrobial candidate selection from informed d-/l-Peptide dimer libraries.
abstract: Growing resistance to antibiotics, as well as newly emerging pathogens, stimulate the investigation of antimicrobial peptides (AMPs) as therapeutic agents. Here, we report a new library design concept based on a stochastic distribution of natural AMP amino acid sequences onto half-length synthetic peptides. For these compounds, a non-natural motif of alternating D- and L-backbone stereochemistry of the peptide chain predisposed for β-helix formation was explored. Synthetic D-/L-peptides with permuted half-length sequences were delineated from a full-length starter sequence and covalently recombined to create two-dimensional compound arrays for antibacterial screening. Using the natural AMP magainin as a seed sequence, we identified and iteratively optimized hit compounds showing high antimicrobial activity against Gram-positive and Gram-negative bacteria with low hemolytic activity. Cryo-electron microscopy characterized the membrane-associated mechanism of action of the new D-/L-peptide antibiotics.
authors.affiliation: Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany); Current address: Institute of Organic Chemistry, University of Vienna, Währingerstrasse 38, 1090 Wien (Austria).
authors.forename: Roman J
authors.initials: RJ
authors.lastname: Lichtenecker
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ellinger
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Han
authors.forename: Kirtikumar B
authors.initials: KB
authors.lastname: Jadhav
authors.forename: Sascha
authors.initials: S
authors.lastname: Baumann
authors.forename: Oliwia
authors.initials: O
authors.lastname: Makarewicz
authors.forename: Markus
authors.initials: M
authors.lastname: Grabenbauer
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Arndt
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy; D006801:Humans; D008969:Molecular Sequence Data; D019151:Peptide Library; D060327:Solid-Phase Synthesis Techniques; D013269:Stochastic Processes
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D019151:Peptide Library
keywords: antibiotics; compound libraries; peptides; screening; solid-phase synthesis