Real-time Measurement of Membrane Conformational States Induced by Antimicrobial Peptides: Balance Between Recovery and Lysis

Hall, Kristopher Norman; Lee, Tzong-Hsien; Mechler, Ádám; Swann, Marcus J.; Aguilar, Marie‐Isabel

doi:10.1038/srep05479

Cited by 59 publications

(69 citation statements)

References 48 publications

(96 reference statements)

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“…A detailed description was provided in a previous work29. Briefly, the f-D curve correlates viscoelastic changes to mass uptake, which reflect changes in the membrane organization3548. Thus, each direction in f-D space reveals distinct mechanical changes.…”

Section: Methodsmentioning

confidence: 99%

Membrane Core-Specific Antimicrobial Action of Cathelicidin LL-37 Peptide Switches Between Pore and Nanofibre Formation

Shahmiri

Enciso

Adda

et al. 2016

Sci Rep

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Membrane-disrupting antimicrobial peptides provide broad-spectrum defence against localized bacterial invasion in a range of hosts including humans. The most generally held consensus is that targeting to pathogens is based on interactions with the head groups of membrane lipids. Here we show that the action of LL-37, a human antimicrobial peptide switches the mode of action based on the structure of the alkyl chains, and not the head groups of the membrane forming lipids. We demonstrate that LL-37 exhibits two distinct interaction pathways: pore formation in bilayers of unsaturated phospholipids and membrane modulation with saturated phospholipids. Uniquely, the membrane modulation yields helical-rich fibrous peptide-lipid superstructures. Our results point at alternative design strategies for peptide antimicrobials.

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Section: Methodsmentioning

confidence: 99%

Membrane Core-Specific Antimicrobial Action of Cathelicidin LL-37 Peptide Switches Between Pore and Nanofibre Formation

Shahmiri

Enciso

Adda

et al. 2016

Sci Rep

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“…Antimicrobial peptides that are known to induce membrane disruption act on the inner/cytoplasmic membrane, which is known to contain disulfide bond-reducing proteins and have a redox potential that favors disulfide bond disruption (Eser et al, 2009;Kadokura et al, 2003). Furthermore, the bacterial membrane is highly fluid and dynamic, and the lytic action of some AMPs has been shown to be reversible (Gee et al, 2013;Hall et al, 2014;Lee et al, 2014). Thus the decline in activity from that measured by flow cytometry (MPC) and that measured by the growth assays (MIC and MBC) is probably due to two factors: the fluid/dynamic nature and disulfide bond-reducing environment of the inner membrane.…”

Section: Synthesis Of Chex-arg20 Multimer Analogsmentioning

confidence: 98%

Multimerization of a Proline-Rich Antimicrobial Peptide, Chex-Arg20, Alters Its Mechanism of Interaction with the Escherichia coli Membrane

O'Brien-Simpson

Tailhades

et al. 2015

Chemistry & Biology

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A3-APO, a de novo designed branched dimeric proline-rich antimicrobial peptide (PrAMP), is highly effective against a variety of in vivo bacterial infections. We undertook a selective examination of the mechanism for the Gram-negative Escherichia coli bacterial membrane interaction of the monomer (Chex-Arg20), dimer (A3-APO), and tetramer (A3-APO disulfide-linked dimer). All three synthetic peptides were effective at killing E. coli. However, the tetramer was 30-fold more membrane disruptive than the dimer while the monomer showed no membrane activity. Using flow cytometry and high-resolution fluorescent microscopy, it was observed that dimerization and tetramerization of the Chex-Arg20 monomer led to an alteration in the mechanism of action from non-lytic/membrane hyperpolarization to membrane disruption/depolarization. Our findings show that the membrane interaction and permeability of Chex-Arg20 was altered by multimerization.

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“…The mass of an adsorbed molecular layer was calculated with the use of the De Feijter formula (42) where the dn/dc values of 0.135 and 0.182 ml/g were used for calculating the adsorbed lipids and peptides, respectively (43,44). Birefringence (⌬n f ) was obtained by calculating the difference between two effective refractive indices, namely refractive index of transverse magnetic (TM) waveguide mode (n TM ) and refractive index of transverse electric (TE) waveguide mode (n TE ) (43)(44)(45). The respective effective adlayers n TM and n TE corresponding to the measured TM and TE phase changes are calculated by fitting data to a waveguide equation (44 -46).…”

Section: Methodsmentioning

confidence: 99%

Development of a μO-Conotoxin Analogue with Improved Lipid Membrane Interactions and Potency for the Analgesic Sodium Channel NaV1.8

Deuis

Dekan

Inserra

et al. 2016

Journal of Biological Chemistry

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The O-conotoxins MrVIA, MrVIB, and MfVIA inhibit the voltage-gated sodium channel Na V 1.8, a well described target for the treatment of pain; however, little is known about the residues or structural elements that define this activity. In this study, we determined the three-dimensional structure of MfVIA, examined its membrane binding properties, performed alaninescanning mutagenesis, and identified residues important for its activity at human Na V 1.8. A second round of mutations resulted in (E5K,E8K)MfVIA, a double mutant with greater positive surface charge and greater affinity for lipid membranes compared with MfVIA. This analogue had increased potency at Na V 1.8 and was analgesic in the mouse formalin assay.Voltage-gated sodium channels (Na V s) 5 are responsible for the initiation and propagation of action potentials (1). Nine subtypes have been described to date (Na V 1.1-1.9), each with a distinct expression profile and subsequent functional role (1). For example, Na V 1.4 is predominantly expressed in skeletal muscle where it is important in the generation and propagation of action potentials that initiate muscle contraction (2), whereas Na V 1.5 is predominately expressed in cardiac tissue where it is crucial in setting the electrical conduction properties of the heart (3). Several subtypes (Na V 1.1 and Na V 1.6 -1.9) are expressed in peripheral sensory neurons, and it is due to this expression profile that some of these subtypes have gained attention as potential therapeutic targets for pain (4). Na V 1.8 is of particular interest as an analgesic target because it is expressed almost exclusively in peripheral sensory neurons and is present in the majority of nociceptive neurons (5, 6) where it is a major contributor to the sodium current underlying action potentials (7-9). Accordingly, Na V 1.8-null mice have reduced responses to nociceptive mechanical and thermal stimuli as well as deficits in the development of inflammatory pain, visceral pain, and to a lesser extent neuropathic pain (10 -14). Therefore, pharmacological inhibition of Na V 1.8 is considered a promising therapeutic strategy for the treatment of pain.The recently discovered O-conotoxin MfVIA (15) and the related MrVIA and MrVIB (16) (see Fig. 1A) are some of a few venom-derived peptides that inhibit Na V 1.8 and the only peptides known to selectively inhibit Na V 1.8 over the other neuronal Na V subtypes expressed in peripheral sensory neurons (15,17,18). However, despite this unique selectivity, little is known about structure-activity relationships of the O-conotoxins. This gap in knowledge arises from difficulties in the synthesis of sufficient quantities to permit detailed studies (19), which is in part due to the hydrophobic nature of these peptides. Characterization of the structural elements contributing to the high affinity inhibition of Na V 1.8 by the O-conotoxins is of particular interest given that the O-conotoxins also potently inhibit the skeletal muscle isoform Na V 1.4, and reduced activity at Na V 1.4 while maintain...

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Real-time Measurement of Membrane Conformational States Induced by Antimicrobial Peptides: Balance Between Recovery and Lysis

Cited by 59 publications

References 48 publications

Membrane Core-Specific Antimicrobial Action of Cathelicidin LL-37 Peptide Switches Between Pore and Nanofibre Formation

Membrane Core-Specific Antimicrobial Action of Cathelicidin LL-37 Peptide Switches Between Pore and Nanofibre Formation

Multimerization of a Proline-Rich Antimicrobial Peptide, Chex-Arg20, Alters Its Mechanism of Interaction with the Escherichia coli Membrane

Development of a μO-Conotoxin Analogue with Improved Lipid Membrane Interactions and Potency for the Analgesic Sodium Channel NaV1.8

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