title: Design and characterization of novel hybrid antimicrobial peptides based on cecropin A, LL-37 and magainin II.
abstract: Antimicrobial peptides (AMPs) are a naturally occurring component of the innate immune response of many organisms and can have activity against both Gram-negative and Gram-positive bacterial species. In order to optimize and improve the direct antimicrobial effect of AMPs against a broad spectrum of bacterial species, novel synthetic hybrids were rationally designed from cecropin A, LL-37 and magainin II. AMPs were selected based on their α-helical secondary structure and fragments of these were analyzed and combined in silico to determine which hybrid peptides would form the best amphipathic cationic α-helices. Four hybrid peptides were synthesized (CaLL, CaMA, LLaMA and MALL) and evaluated for direct antimicrobial activity against a range of bacterial species (Bacillus anthracis, Burkholderia cepacia, Francisella tularensis LVS and Yersinia pseudotuberculosis) alongside the original 'parent' AMPs. The hybrid peptides showed greater antimicrobial effects than the parent AMPs (in one case a parent is completely ineffective while a hybrid based on it removes all traces of bacteria by 3h), although they also demonstrated higher hemolytic properties. Modifications were then carried out to the most toxic hybrid AMP (CaLL) to further improve the therapeutic index. Modifications made to the hybrid lowered hemolytic activity and also lowered antimicrobial activity by various degrees. Overall, this work highlights the potential for rational design and synthesis of improved AMPs that have the capability to be used therapeutically for treatment of bacterial infections.
authors.affiliation: Department of Biomedical Sciences, Defence Science and Technology Laboratory, Porton Down, Salisbury, Wiltshire SP4 0JQ, UK. mafox@dstl.gov.uk
authors.forename: Marc A
authors.initials: MA
authors.lastname: Fox
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Thwaite
authors.forename: David O
authors.initials: DO
authors.lastname: Ulaeto
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Atkins
authors.forename: Helen S
authors.initials: HS
authors.lastname: Atkins
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*; D001408:Bacillus anthracis / Q000187:drug effects; D016956:Burkholderia cepacia / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects; D005604:Francisella tularensis / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D054806:Magainins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D029867:Xenopus Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015011:Yersinia pseudotuberculosis / Q000187:drug effects; D054804:Cathelicidins
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D054806:Magainins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D029867:Xenopus Proteins; C053301:magainin 2 peptide, Xenopus; C031161:cecropin A; D054804:Cathelicidins