Cell membrane models for investigating the mechanisms of action of antimicrobial peptides and the effects from dimerization and cyclization

Abstract

Langmuir monolayers and vesicles are useful cell membrane models, with which the interactions with pharmaceutical drugs can be determined and correlated with the effects induced in the membrane. In this Project, we shall study the biological activity of antimicrobial peptides (PAMs) and their mechanism of action with Langmuir monolayers and unilamellar vesicles of various lipid compositions to mimic biomembranes of bacteria and mammals. PAMs were selected because they are toxic to microorganisms and tumor cells, with high selectivity and low probability of developing resistance. As starting point, we shall use the dimeric peptide of Magainin 2, (MG2)2K, whose activity against Escherichia coli and Staphylococcus aureus was 16 and 8 times the value for its monomeric version, respectively. Cyclic and dimeric versions of (MG2)2K and other peptides will be synthesized and studied for the effect of these modifications on the activity against multi-resistant nosocomial pathogens and tumor cells. The interaction between peptides and the Langmuir monolayers will be studied with surface pressure isotherms, polarization-modulated infrared reflection-absorption spectroscopy (PM-IRRAS), and Brewster angle microscopy, while for the vesicles use will be made of phase contrast microscopy and fluorescence. With the combination of these techniques, we aim at developing new bioactive molecules and determine their mechanism of action accounting for the biological activity.