Different mechanisms of action of antimicrobial peptides: insights from fluorescence spectroscopy experiments and molecular dynamics simulations

Abstract

Most antimicrobial peptides exert their activity by interacting with bacterial membranes, thus perturbing their permeability. They are investigated as a possible solution to the insurgence of bacteria resistant to the presently available antibiotic drugs. However, several different models have been proposed for their mechanism of membrane perturbation, and the molecular details of this process are still debated. Here, we compare fluorescence spectroscopy experiments and molecular dynamics (MD) simulations regarding the association with lipid bilayers and lipid perturbation for two different amphiphilic helical antimicrobial peptides, PMAP-23 and trichogin GA IV. PMAP-23, a cationic peptide member of the cathelicidin family, is considered to induce membrane permeability according to the Shai-Matsuzaki-Huang ''carpet'' model, while trichogin GA IV is a neutral peptide, member of the peptaibol family. Although several lines of evidence suggest a ''barrel-stave'' mechanism of pore formation for the latter peptide, its length is only half the normal thickness of a lipid bilayer. Both fluorescence spectroscopy experiments and MD simulations indicated that PMAP-23 associates with membranes close to their surface and parallel to it, and in this arrangement it causes a severe perturbation to the bilayer, both regarding its surface tension and lipid order. By contrast, trichogin GA IV can undergo a transition from a surface-bound state to a transmembrane orientation. In the first arrangement, it does not cause any strong membrane perturbation, while in the second orientation it might be able to span the bilayer from one side to the other, despite its relatively short length, by causing a significant thinning of the membrane.

Hypersensitive‐Like Response to the Pore‐Former Peptaibol Alamethicin in Arabidopsis Thaliana

“…This finding favors the conclusion that this bioactivity is associated with a transmembrane orientation of the peptide, and with an initial pore-forming mechanism in which the peptide hydrophobic length has to match the membrane width. Recently, Bocchinfuso et al [54] demonstrated that, despite its short length, the natural ten-amino acid-long trichogin GA IV is able to span the membrane bilayer by causing a local thinning. The N-1-octanoylated (GLUG) n methyl esters tested in this work have also been shown to form pores in artificial membranes.…”

Through the Lipopolysaccharide Glass: A Potent Antimicrobial Peptide Induces Phase Changes in Membranes

“…[8,9]. While computer simulation, particularly at the molecular level is potentially a powerful tool for the development of targeted and cost-effective novel therapies it is somewhat hampered by our lack of understanding of the molecular pathways utilized by antibiotics to both enter and destroy bacterial cells [10][11][12][13][14][15]. To further this understanding, simulation of currently used antibiotics with biologically relevant models of bacterial membranes is imperative.…”

Natural Antimicrobial Peptides from Eukaryotic Organisms

“…Then permeabilization occurs, via global bilayer destabilization. PMAP-23, a cationic peptide member of the cathelicidin family, is considered to induce membrane permeability according to the Shai-Matsuzaki-Huang "carpet" model (Bocchinfuso et al, 2009). Cecropin P1, another alpha helical AMP, imbedded in reconstituted phospholipid bilayer is preferentially oriented nearly parallel to the surface of the lipid membranes, a position that is incompatible with the proteinaceous pore model, as demonstrated by polarized ATR-FTIR spectroscopy analysis (Gazit et al, 1996) The detergent model is also often cited to explain the catastrophic collapse of membrane integrity, observed with some AMPs at high peptide concentration (Ostolaza et al, 1993;Hristova et al, 1997;Bechinger and Lohner, 2006).…”