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Antimicrobial Peptides - Interaction with Membrane Lipids and Proteins

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Antimicrobial peptides (AMPs) occur naturally in all domains of life and constitute one of the oldest host-defense strategies. As part of the innate immune system they combat bacteria, fungi, viruses, and even cancer cells. In addition to direct antimicrobial action, mammalian AMPs often additionally display ...

Antimicrobial peptides (AMPs) occur naturally in all domains of life and constitute one of the oldest host-defense strategies. As part of the innate immune system they combat bacteria, fungi, viruses, and even cancer cells. In addition to direct antimicrobial action, mammalian AMPs often additionally display immune-modulatory properties. Facing the current antibacterial resistance crisis, AMPs might contribute to finding new antibacterial strategies.

Although structurally and mechanistically diverse, a majority of peptides exert antimicrobial action at the cell surface, directly targeting lipids or membrane-bound components, e.g. cell wall precursors. So far, most mechanistic studies on the antimicrobial mechanisms of membrane-targeting peptides have been focused on their interaction with artificial lipid systems. Various mode of action models have been proposed. Classical pore forming models, like the barrel-stave, toroidal pore or carpet models, provide insight into interaction of amphipathic alpha-helical peptides with lipid bilayers. These models do not work for smaller or more compact peptides that are unable to span the lipid bilayer and form a pore. Alternative explanations for pore formation include the molecular electroporation, sinking raft, interfacial activity, and lipocentric pore formation models. All of them are also applicable to smaller AMPs.

While all these studies provide valuable insight into the interaction of AMPs with lipid bilayers, translation of these models into the natural in vivo situation might be difficult. Biological membranes have a more complex lipid composition than can be mimicked in model studies. Furthermore, biological systems are highly dynamic and membrane composition vary substantially depending on the environmental conditions. Lipid domains of reduced or increased fluidity as well as membrane curvature play crucial roles in membrane functionality. Maybe even more importantly, a biological membrane is not only composed of lipids but also of up to 60% protein, a fact that is often times neglected, when it comes to explaining AMP action on membranes.

So far, in vivo studies on AMP action are scarce and often limited to characterization of their pore-forming abilities. However, the formation of pores is concentration-dependent and often sub pore-forming doses are already inhibitory. There are also very small AMPs that do not affect membrane permeability. Thus, the inhibitory interactions taking place at the membrane level cannot be fully explained with the current pore formation models.

In order to thoroughly understand the in vivo mechanism of action of AMPs, it is necessary to view biological membranes as a whole, including membrane organization and protein localization. Therefore, it is crucial to combine knowledge from in vitro studies on model systems with in vivo studies on the physiological impact on the targeted cell. This Research Topic aims to bring together cell-based and molecular approaches to understand the impact of AMPs on both lipid and protein components of biological membranes.


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