title: Destabilization of α-Helical Structure in Solution Improves Bactericidal Activity of Antimicrobial Peptides: Opposite Effects on Bacterial and Viral Targets.
abstract: We have previously examined the mechanism of antimicrobial peptides on the outer membrane of vaccinia virus. We show here that the formulation of peptides LL37 and magainin-2B amide in polysorbate 20 (Tween 20) results in greater reductions in virus titer than formulation without detergent, and the effect is replicated by substitution of polysorbate 20 with high-ionic-strength buffer. In contrast, formulation with polysorbate 20 or high-ionic-strength buffer has the opposite effect on bactericidal activity of both peptides, resulting in lesser reductions in titer for both Gram-positive and Gram-negative bacteria. Circular dichroism spectroscopy shows that the differential action of polysorbate 20 and salt on the virucidal and bactericidal activities correlates with the α-helical content of peptide secondary structure in solution, suggesting that the virucidal and bactericidal activities are mediated through distinct mechanisms. The correlation of a defined structural feature with differential activity against a host-derived viral membrane and the membranes of both Gram-positive and Gram-negative bacteria suggests that the overall helical content in solution under physiological conditions is an important feature for consideration in the design and development of candidate peptide-based antimicrobial compounds.
authors.affiliation: CBR Division, Dstl Porton Down, Salisbury, United Kingdom dulaeto@dstl.gov.uk.
authors.forename: David O
authors.initials: DO
authors.lastname: Ulaeto
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Morris
authors.affiliation: CBR Division, Dstl Porton Down, Salisbury, United Kingdom.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Fox
authors.affiliation: College of Biomedical and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Gumbleton
authors.affiliation: College of Biomedical and Life Sciences, School of Dentistry, Cardiff University, Cardiff, United Kingdom.
authors.forename: Konrad
authors.initials: K
authors.lastname: Beck
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D054804:Cathelicidins / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects / Q000821:virology; D004926:Escherichia coli / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D008826:Microbial Sensitivity Tests; D009994:Osmolar Concentration; D011136:Polysorbates / Q000737:chemistry / Q000494:pharmacology*; D000072756:Protein Conformation, alpha-Helical / Q000187:drug effects; D011817:Rabbits; D013045:Species Specificity; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship; D014616:Vaccinia virus / Q000187:drug effects* / Q000254:growth & development; D014771:Virion / Q000187:drug effects / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D000998:Antiviral Agents; D054804:Cathelicidins; D011136:Polysorbates; C066945:magainin B
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