Antimicrobial Peptide Structures: From Model Membranes to Live Cells

Sani, Marc‐Antoine; Separovic, Frances

doi:10.1002/chem.201704362

Cited by 25 publications

(12 citation statements)

References 54 publications

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“…Only few years after the discovery of magainins solid-state NMR experiments on these peptides reconstituted into uniaxially oriented lipid bilayers indicated for the very first time that they adopt stable alignments parallel to the membrane surface (Bechinger et al 1990(Bechinger et al , 1991a(Bechinger et al , b, 1992(Bechinger et al , 1993. This topology has been confirmed for magainin 2 in all lipid compositions investigated so far , for magainin analogues (Ramamoorthy et al 2006;Mason et al 2009), and for several other linear cationic antimicrobial peptides (Resende et al 2009(Resende et al , 2014Hayden et al 2015;Bechinger and Gorr 2017;Sani and Separovic 2018). Furthermore, oriented CD spectra agree with such an alignment of the magainin helix (Ludtke et al 1994).…”

Section: Solid-state Nmr Investigations Of Polypeptidessupporting

confidence: 61%

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

Aisenbrey¹,

Marquette²,

Bechinger³

2019

Advances in Experimental Medicine and Biology

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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

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Section: Solid-state Nmr Investigations Of Polypeptidessupporting

confidence: 61%

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

Aisenbrey¹,

Marquette²,

Bechinger³

2019

Advances in Experimental Medicine and Biology

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“…Importantly, both circular dichroism (CD) and solid-state nuclear magnetic resonance (NMR) spectroscopy on uniaxially oriented membranes indicate that the magainin helix is oriented parallel to the membrane surface, which results in membrane association being reversible [ 38 ]. The in-planar alignment has been confirmed for magainin 2 in membranes of different composition [ 38 , 54 ], for magainin analogues [ 80 , 81 ] and for a number of other linear cationic antimicrobial peptides [ 82 , 83 , 84 , 85 , 86 ]. In contrast, alamethicin with its much different characteristics in both electrophysiological recordings and physico-chemical properties ( Table 1 ), has been found to form well-defined channels (reviewed e.g., in [ 17 , 87 ]) and to adopt stable transmembrane helical alignments in canonical dimyristoyl-phosphatidylcholine (DMPC) and (POPC) membranes [ 88 , 89 , 90 , 91 , 92 ].…”

Section: Introductionmentioning

confidence: 95%

Biophysical Investigations Elucidating the Mechanisms of Action of Antimicrobial Peptides and Their Synergism

Marquette

Bechinger

2018

Biomolecules

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Biophysical and structural investigations are presented with a focus on the membrane lipid interactions of cationic linear antibiotic peptides such as magainin, PGLa, LL37, and melittin. Observations made with these peptides are distinct as seen from data obtained with the hydrophobic peptide alamethicin. The cationic amphipathic peptides predominantly adopt membrane alignments parallel to the bilayer surface; thus the distribution of polar and non-polar side chains of the amphipathic helices mirror the environmental changes at the membrane interface. Such a membrane partitioning of an amphipathic helix has been shown to cause considerable disruptions in the lipid packing arrangements, transient openings at low peptide concentration, and membrane disintegration at higher peptide-to-lipid ratios. The manifold supramolecular arrangements adopted by lipids and peptides are represented by the ‘soft membranes adapt and respond, also transiently’ (SMART) model. Whereas molecular dynamics simulations provide atomistic views on lipid membranes in the presence of antimicrobial peptides, the biophysical investigations reveal interesting details on a molecular and supramolecular level, and recent microscopic imaging experiments delineate interesting sequences of events when bacterial cells are exposed to such peptides. Finally, biophysical studies that aim to reveal the mechanisms of synergistic interactions of magainin 2 and PGLa are presented, including unpublished isothermal titration calorimetry (ITC), circular dichroism (CD) and dynamic light scattering (DLS) measurements that suggest that the peptides are involved in liposome agglutination by mediating intermembrane interactions. A number of structural events are presented in schematic models that relate to the antimicrobial and synergistic mechanism of amphipathic peptides when they are aligned parallel to the membrane surface.

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“…Because the 15 N chemical shift of peptide bonds alone already provides an approximate tilt angle of helical domains (85) the very first experiments with magainin 2 and PGLa were indicative that these helices are oriented parallel to the membrane surface (63,(86)(87)(88). A membrane alignment parallel to the lipid bilayer surface has been confirmed for magainin 2 (89), for magainin analogs (90,91) and for several other linear cationic antimicrobial peptides (22,(92)(93)(94)(95). Later on oriented CD spectra and fluorescence quenching experiments confirmed such a topology of the magainin helix where the latter approach also shows an interfacial localization of the magainin 2 helix (64,96).…”

Section: Magainin Structural Investigationsmentioning

confidence: 95%

Revealing the Mechanisms of Synergistic Action of Two Magainin Antimicrobial Peptides

Bechinger

Juhl

Glattard

et al. 2020

Front. Med. Technol.

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The study of peptide-lipid and peptide-peptide interactions as well as their topology and dynamics using biophysical and structural approaches have changed our view how antimicrobial peptides work and function. It has become obvious that both the peptides and the lipids arrange in soft supramolecular arrangements which are highly dynamic and able to change and mutually adapt their conformation, membrane penetration, and detailed morphology. This can occur on a local and a global level. This review focuses on cationic amphipathic peptides of the magainin family which were studied extensively by biophysical approaches. They are found intercalated at the membrane interface where they cause membrane thinning and ultimately lysis. Interestingly, mixtures of two of those peptides namely magainin 2 and PGLa which occur naturally as a cocktail in the frog skin exhibit synergistic enhancement of antimicrobial activities when investigated together in antimicrobial assays but also in biophysical experiments with model membranes. Detailed dose-response curves, presented here for the first time, show a cooperative behavior for the individual peptides which is much increased when PGLa and magainin are added as equimolar mixture. This has important consequences for their bacterial killing activities and resistance development. In membranes that carry unsaturations both peptides align parallel to the membrane surface where they have been shown to arrange into mesophases involving the peptides and the lipids. This supramolecular structuration comes along with much-increased membrane affinities for the peptide mixture. Because this synergism is most pronounced in membranes representing the bacterial lipid composition it can potentially be used to increase the therapeutic window of pharmaceutical formulations.

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Antimicrobial Peptide Structures: From Model Membranes to Live Cells

Cited by 25 publications

References 54 publications

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

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

Biophysical Investigations Elucidating the Mechanisms of Action of Antimicrobial Peptides and Their Synergism

Revealing the Mechanisms of Synergistic Action of Two Magainin Antimicrobial Peptides

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