title: Directed alteration of a novel bovine beta-defensin to improve antimicrobial efficacy against methicillin-resistant Staphylococcus aureus (MRSA).
abstract: beta-Defensin antimicrobial peptides are critical components of the innate immune response in many species and may be useful against pathogens that have acquired resistance to standard antibiotic therapies. We analysed a panel of recently discovered bovine beta-defensins in order to identify sites that may have particular functional importance against antibiotic-resistant bacteria. Modifications were introduced to increase charge at positively selected (PS) sites, to make charge-neutral changes at PS sites, to increase hydrophobicity and to confer a hydrophilic C-terminal. Whilst all four peptide modifications increased antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) compared with the native form of bovine beta-defensin 123 (P=0.02), conferring the hydrophilic tail caused the most significant increase, with a 50% lethal dose (LD(50)) of 3.91 microg/mL. The peptide with increased charge at PS sites showed the most significant increase in antimicrobial activity against a non-resistant strain of S. aureus (P=0.02). Therefore, informed modifications of the amino acid sequence can significantly affect the specificity and antimicrobial activity of a peptide.
authors.affiliation: Comparative Immunology Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.
authors.forename: Kieran G
authors.initials: KG
authors.lastname: Meade
authors.forename: Sarah
authors.initials: S
authors.lastname: Cahalane
authors.forename: Fernando
authors.initials: F
authors.lastname: Narciandi
authors.forename: Paul
authors.initials: P
authors.lastname: Cormican
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Lloyd
authors.forename: Cliona
authors.initials: C
authors.lastname: O'Farrelly
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002417:Cattle; D019295:Computational Biology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023083:beta-Defensins / Q000235:genetics* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D010455:Peptides; D023083:beta-Defensins