The Mechanisms of Action of Cationic Antimicrobial Peptides Refined by Novel Concepts from Biophysical Investigations

Abstract

Even 30 years after the discovery of magainins, biophysical and structural investigations on how these peptides interact with membranes can still bear surprises and add new interesting detail to how these peptides exert their antimicrobial action. Early on, using oriented solid-state NMR spectroscopy, it was found that the amphipathic helices formed by magainins are active when being oriented parallel to the membrane surface. More recent investigations indicate that this in-planar alignment is also found when PGLa and magainin in combination exert synergistic pore-forming activities, where studies on the mechanism of synergistic interaction are ongoing. In a related manner, the investigation of dimeric antimicrobial peptide sequences has become an interesting topic of research which bears promise to refine our views how antimicrobial action occurs. The molecular shape concept has been introduced to explain the effects of lipids and peptides on membrane morphology, locally and globally, and in particular of cationic amphipathic helices that partition into the membrane interface. This concept has been extended in this review to include more recent ideas on soft membranes that can adapt to external stimuli including membrane-disruptive molecules. In this manner, the lipids can change their shape in the presence of low peptide concentrations, thereby maintaining the bilayer properties. At higher peptide concentrations, phase transitions occur which lead to the formation of pores and membrane lytic processes. In the context of the molecular shape concept, the properties of lipopeptides, including surfactins, are shortly presented, and comparisons with the hydrophobic alamethicin sequence are made. Keywords (separated by "-") Magainin-PGLa-Cecropin-LL37-Surfacting alamethicin-Membrane topology-Membrane pore-Membrane macroscopic phase-SMART model-Carpet model-Toroidal pore-Peptide-lipid interactions-Molecular shape concept

Solid-State NMR Investigations of the MHC II Transmembrane Domains: Topological Equilibria and Lipid Interactions

“…7h). Therefore, DQB1 in combination with the SM lipid exerts a membrane disordering efect similar to changes that have previously been observed for linear cationic amphipathic antimicrobial peptides such as magainins (Aisenbrey et al 2019;Grage et al 2016;Hallock et al 2003;Harmouche and Bechinger 2018;Kim et al 2009;Salnikov et al 2010). Whereas these antimicrobial peptides are oriented along the bilayer interface where they induce pronounced positive curvature strain (Aisenbrey et al 2019;Bechinger 2009), DQA1 and DQB1 adopt transmembrane but strongly tilted arrangements (Fig.…”

Trichogin GA IV Alignment and Oligomerization in Phospholipid Bilayers

“…However, membrane passage of rather bulky molecules has been observed in fluorophore‐release experiments in the absence of transmembrane electric fields; this is indicative of helical bundles of considerable dimensions or of membrane perturbations involving supramolecular peptide–lipid arrangements such as those shown in Figure B and C . Thus, the shorter peptaibols preferentially align parallel to the membrane surface, as observed for cationic amphipathic peptides .…”

Copper-binding motifs Xxx-His or Xxx-Zzz-His (ATCUN) linked to an antimicrobial peptide: Cu-binding, antimicrobial activity and ROS production

“…Antimicrobial peptides are classically small peptides (up to 50 amino acids long), cationic and target different type of microorganisms [11][12][13]. Their mechanism of action is mostly based on the interaction with membranes, which are classically more negatively charged in bacteria than in eukaryotes [14]. Different membrane interactions and toxicity mechanisms are reported, such as destabilization or disruption of the membrane, pore formation, and penetration into the cell interior [11].…”