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Molecular Basis of Selectivity and Activity for the Antimicrobial Peptide Lynronne‐1 Informs Rational Design of Peptide with Improved Activity
Author(s) -
Jayawant Eleanor S.,
Hutchinson Jack,
Gašparíková Dorota,
Lockey Christine,
Pruñonosa Lara Lidón,
Guy Ciaran,
Brooks Rhian L.,
Dixon Ann M.
Publication year - 2021
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.202100151
Subject(s) - acinetobacter baumannii , antimicrobial peptides , antimicrobial , peptide , chemistry , magainin , combinatorial chemistry , biochemistry , rational design , amphiphile , lysis , natural product , biophysics , bacteria , biology , pseudomonas aeruginosa , organic chemistry , copolymer , polymer , genetics
Antibiotic resistance is a significant threat to human health, with natural products remaining the best source for new antimicrobial compounds. Antimicrobial peptides (AMPs) are natural products with great potential for clinical use as they are small, amenable to customization, and show broad‐spectrum activities. Lynronne‐1 is a promising AMP identified in the rumen microbiome that shows broad‐spectrum activity against pathogens such as methicillin‐resistant Staphylococcus aureus and Acinetobacter baumannii . Here we investigated the structure of Lynronne‐1 using solution NMR spectroscopy and identified a 13‐residue amphipathic helix containing all six cationic residues. We used biophysical approaches to observe folding, membrane partitioning and membrane lysis selective to the presence of anionic lipids. We translated our understanding of Lynronne‐1 structure to design peptides which varied in the size of their hydrophobic helical face. These peptides displayed the predicted continuum of membrane‐lysis activities in vitro and in vivo , and yielded a new AMP with 4‐fold improved activity against A. baumannii and 32‐fold improved activity against S. aureus .