Abstract
Peptide–lipid interactions support a variety of biological functions. Of particular interest are those that underpin fundamental mechanisms of innate immunity that are programmed in host defense or antimicrobial peptide sequences found virtually in all multicellular organisms. Here we synthetically modulate antimicrobial peptide–lipid interactions using an archetypal helical antimicrobial peptide and synthetic membranes mimicking bacterial and mammalian membranes in solution. We probe these interactions as a function of membrane-induced folding, membrane stability and peptide–lipid ratios using a correlative approach encompassing light scattering and spectroscopy measurements such as circular dichroism spectroscopy, fluorescence and nuclear magnetic resonance spectroscopy. The peptide behavior is assessed against that of its anionic counterpart having similar propensities for α-helical folding. The results indicate strong correlations between peptide folding and membrane type, supporting folding-responsive binding of antimicrobial peptides to bacterial membranes. The study provides a straightforward approach for modulating structure–activity relationships in the context of membrane-induced antimicrobial action, thus holding promise for the rational design of potent antimicrobial agents.
Highlights
Antimicrobial peptides (AMPs) are universal effector molecules of innate immunity found in all multicellular organisms (Brogden 2005)
Using two types of reconstituted model membranes mimicking bacterial and mammalian membranes, respectively, which were assembled from two different phospholipid compositions, saturated and unsaturated lipids, we have performed a comparative assessment of these interactions for both active and inactive peptide forms, i.e., (+)-helix and (−)-helix
The study confirmed the overarching concept of antimicrobial peptides being able to induce membrane perturbations and subsequent disintegration by incorporating into anionic phospholipid membranes. 1H-nuclear magnetic resonance (1H-NMR) spectra suggested interfacial peptide binding at the expense of decreased mobility of phospholipid headgroups in the anionic and relatively rigid PO membranes
Summary
Antimicrobial peptides (AMPs) are universal effector molecules of innate immunity found in all multicellular organisms (Brogden 2005). AMPs, most of which are cationic, recognize and bind to anionic microbial membranes, whereupon they fold as amphipathic structures whose hydrophobic faces incorporate into phospholipid bilayer interfaces causing membrane disruption and collapse Acquiring resistance against such formidable membrane-active agents is an extremely high price for microorganisms to pay. It is not surprising that the peptides are increasingly considered as next-generation antibiotics (Fjell et al 2012; Giuliani and Rinaldi 2011) As fundamental as their mode of action can be, AMPs largely rely on peptide–lipid interactions. The preference of one mechanism over another appears to depend on several factors, mainly structural features programmed in peptide sequences and how these features respond to lipid binding In this regard, it is important to develop a thorough understanding of the structure–activity relationships of membrane-associated AMPs, which may underpin the development of more powerful and efficient alternatives to conventional antibiotics. The activity of the AMP was assessed against that of its anionic counterpart, which has a similar propensity
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