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 veryhigh concentrations. This analog displays an additional positive charge near the N-terminus (108) and anextra Trp residue at the center of the molecule (111), indicating that this particular amino acid sequenceimproves its interaction with the bacterial plasma membrane. In order to understand the role of thisarrangement in the membrane interaction, studies with model lipid membranes were carried out.The interactions of peptides, 107–115 hLz and the novel analog ([K108W111]107–115 hLz) with lipo-somes and lipid monolayers were evaluated by monitoring the changes in the fluorescence of the Trpresidues and the variation of the monolayers surface pressure, respectively. Results obtained with bothtechniques revealed a significant affinity increase of [K108W111]107–115 hLz for lipids, especially whenthe membranes containing negatively charged lipids, such as phosphatidylglycerol. However, there is alsoa significant interaction with zwitterionic lipids, suggesting that other forces in addition to electrostaticinteractions are involved in the binding. The analysis of adsorption isotherms and the insertion kineticssuggest that relaxation processes of the membrane structure are involved in the insertion process ofnovel peptide [K108W111]107–115 hLz but not in 107–115 hLz, probably by imposing a reorganization ofwater at the interphases.In this regard, the enhanced activity of peptide [K108W111]107–115 hLz may be explained by a syner-gistic effect between the increased electrostatic forces as well as the increased hydrophobic interactions.