title: Biological activity of antibacterial peptides matches synergism between electrostatic and non electrostatic forces.
abstract: Substitution of Ala 108 and Ala 111 in the 107-115 human lysozyme (hLz) fragment results in a 20-fold increased anti-staphylococcal activity while its hemolytic activity becomes significant (30%) at very high concentrations. This analog displays an additional positive charge near the N-terminus (108) and an extra Trp residue at the center of the molecule (111), indicating that this particular amino acid sequence improves its interaction with the bacterial plasma membrane. In order to understand the role of this arrangement in the membrane interaction, studies with model lipid membranes were carried out. The interactions of peptides, 107-115 hLz and the novel analog ([K(108)W(111)]107-115 hLz) with liposomes and lipid monolayers were evaluated by monitoring the changes in the fluorescence of the Trp residues and the variation of the monolayers surface pressure, respectively. Results obtained with both techniques revealed a significant affinity increase of [K(108)W(111)]107-115 hLz for lipids, especially when the membranes containing negatively charged lipids, such as phosphatidylglycerol. However, there is also a significant interaction with zwitterionic lipids, suggesting that other forces in addition to electrostatic interactions are involved in the binding. The analysis of adsorption isotherms and the insertion kinetics suggest that relaxation processes of the membrane structure are involved in the insertion process of novel peptide [K(108)W(111)]107-115 hLz but not in 107-115 hLz, probably by imposing a reorganization of water at the interphases. In this regard, the enhanced activity of peptide [K(108)W(111)]107-115 hLz may be explained by a synergistic effect between the increased electrostatic forces as well as the increased hydrophobic interactions.
authors.affiliation: Laboratory of Biointerfaces and Biomimetic Systems, CITSE-University of Santiago del Estero, 4200 Santiago del Estero and CONICET, Argentina.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Bouchet
authors.affiliation: School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires 1113, Argentina; Therapeutic Peptides Research and Development Laboratory, Chemo-Romikin, 1605 Buenos Aires, Argentina.
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Iannucci
authors.affiliation: School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires 1113, Argentina.
authors.forename: María B
authors.initials: MB
authors.lastname: Pastrian
authors.affiliation: School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires 1113, Argentina.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Cascone
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisbon, Portugal.
authors.forename: Nuno C
authors.initials: NC
authors.lastname: Santos
authors.affiliation: Laboratory of Biointerfaces and Biomimetic Systems, CITSE-University of Santiago del Estero, 4200 Santiago del Estero and CONICET, Argentina.
authors.forename: Edgardo A
authors.initials: EA
authors.lastname: Disalvo
authors.affiliation: Laboratory of Biointerfaces and Biomimetic Systems, CITSE-University of Santiago del Estero, 4200 Santiago del Estero and CONICET, Argentina; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisbon, Portugal; Laboratory of Molecular Microbiology, Institute of Basic and Applied Microbiology, University of Quilmes, B1876BXD Bernal, Argentina. Electronic address: ahollmann@fm.ul.pt.
authors.forename: Axel
authors.initials: A
authors.lastname: Hollmann
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D005453:Fluorescence; D006801:Humans; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry; D008567:Membranes, Artificial; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D010743:Phospholipids / Q000737:chemistry; D011312:Pressure; D016415:Sequence Alignment; D055672:Static Electricity; D014364:Tryptophan / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D008051:Lipid Bilayers; D008567:Membranes, Artificial; D010455:Peptides; D010743:Phospholipids; D014364:Tryptophan
keywords: Antimicrobial peptide; Lysozyme; Peptide–membrane interactions, Hydrophilic–hydrophobic synergism