Influence of Lysine N^ε-Trimethylation and Lipid Composition on the Membrane Activity of the Cecropin A-Melittin Hybrid Peptide CA(1−7)M(2−9)

Abstract

Although many studies have pointed out the promising role of antimicrobial peptides (AMPs) as therapeutical agents, their translation into clinical research is being slow due to the limitations intrinsic to their peptide nature. A number of structural modifications to overcome this problem have been proposed, leading to enhanced AMP biological lifetimes and therapeutic index. In this work, the interaction between liposomes of different lipidic composition and a set of lysine N(ε)-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 show that trimethylated peptides interact strongly with negatively charged (bacterial cell model) but not with zwitterionic (erythrocyte model) liposomes. These results are in agreement with the reduction of cytotoxicity and 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 evidence that the lipid membrane composition has important implications on AMP membrane activity.

Unravelling a Mechanism of Action for a Cecropin A-Melittin Hybrid Antimicrobial Peptide: The Induced Formation of Multilamellar Lipid Stacks

“…The overall quality of the fitting is acceptable. The partition constant thus obtained agrees with the one previously determined by Time Resolved Fluorescence Spectroscopy, 14 5.1x10 5 (when transformed to M -1 by use of the lipid molar volume). The zeff value found for the effective charge is smaller than the nominal charge (+6), as expected.…”

“…[8][9][10] Their activity has been extensively studied, both on model membranes and on pathogens, and their mechanism of action is thought to rely on membrane disruption due to the formation of toroidal pores and/or detergent-like action. [10][11][12][13][14][15][16][17][18][19][20] Nevertheless, the antimicrobial peptide's mechanism(s) of action remain to be demonstrated, and can vary depending on membrane composition. Model membranes are extremelly helpful for a detailed study of the different variables at stake, and can thus provide very insightful information on AMP mechanism of action and as such contribute to the development of more potent and less toxic antimicrobial peptides.…”

Synthesis, preferred conformation, protease stability, and membrane activity of heptaibin, a medium‐length peptaibiotic

“…However, the relative intensities of the two negative ellipticity maxima in the two negatively charged (DOPE/DOPG and DOPG/CL) model membranes were found to be the opposite to that observed in DOPC/CH. It is reasonable to conclude that only the DOPE/DOPG and DOPG/CL molecules41 are able to interact with and slightly perturb the helical structure occurring in the absence of lipids. It is difficult to attribute the observed CD effect to a single parameter as it is known that the n →π* dichroic band intensity may be altered by a variety of factors (length or distortion of the helix, percentage of 3 10 ‐ versus α‐helix, shortening of the intramolecular CO···HN H‐bonds, peptide self‐association)42–46.…”

Antimicrobial Peptides from Venom: Structure, Function and Toxicity

“…The lipid segregation model is underpinned by peptide-lipid biding, which causes defects in the membrane and results in the intracellular contents leaking out of the cell (Teixeira et al 2010). suggested the lipid segregation model could explain the differences in observable minimum inhibitory concentration (MIC) values between bacterial species for the same peptide, suggesting the contribution of the phospholipids affected the antimicrobial activity.…”

“…The mechanism of action of AMPs has been linked with membrane composition which varies between prokaryotic and eukaryotic species (Teixeira et al 2010).…”