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Iterative Antimicrobial Candidate Selection from Informed D ‐/ L ‐Peptide Dimer Libraries
Author(s) -
Lichtenecker Roman J.,
Ellinger Bernhard,
Han HongMei,
Jadhav Kirtikumar B.,
Baumann Sascha,
Makarewicz Oliwia,
Grabenbauer Markus,
Arndt HansDieter
Publication year - 2013
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201300243
Subject(s) - magainin , antimicrobial peptides , peptide , antimicrobial , dimer , peptide sequence , chemistry , biochemistry , bacteria , combinatorial chemistry , biology , computational biology , microbiology and biotechnology , gene , genetics , organic chemistry
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.