Although many studies have pointed out the promising role of antimicrobial peptides (AMPs) as therapeuticalagents, their translation into clinical research is being slow due to the limitations intrinsic to their peptidenature. A number of structural modifications to overcome this problem have been proposed, leading to enhancedAMP biological lifetimes and therapeutic index. In this work, the interaction between liposomes of differentlipidic composition and a set of lysine N#949;-trimethylated analogs of the cecropin A and melittin hybrid peptide,CA(1-7)M(2-9) [H-KWKLFKKIGAVLKVL-amide], was studied by differential scanning calorimetry (DSC)and fluorescence spectroscopy. The study was carried out using membrane models for mammalian erythrocytes(zwitterionic lipids) and for bacteria (mixture of zwitterionic and negatively charged lipids). The results showthat trimethylated peptides interact strongly with negatively charged (bacterial cell model) but not withzwitterionic (erythrocyte model) liposomes. These results are in agreement with the reduction of cytotoxicityand ensuing improvement in therapeutic index vs parental CA(1-7)M(2-9) found in a related study. Moreover,the modified peptides act differently depending on the model membrane used, providing further evidencethat the lipid membrane composition has important implications on AMP membrane activity.