Structure, Antimicrobial Activities and Mode of Interaction with Membranes of Bovel Phylloseptins from the Painted-Belly Leaf Frog, Phyllomedusa sauvagii

Raja, Zahid; André, Sónia; Piesse, Christophe; Sereno, Denis; Nicolas, Pierre; Foulon, Thierry; Oury, Bruno; Ladram, Ali

doi:10.1371/journal.pone.0070782

Cited by 27 publications

(35 citation statements)

References 40 publications

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“…The homogeneity and identity of the synthetic peptides were assessed by analytical reversed-phase high-performance liquid chromatography (RP-HPLC) on a C18 analytical column (Modulo-cart QS Uptisphere 5 ODB, 5 mm, 250 x 4.6 mm, Interchim, Montluçon, France) and by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry carried out on a Voyager-DE PRO (Applied Biosystems, Foster City, CA, USA) under the same conditions as described previously (Mass Spectrometry and Proteomics Platform, IBPS, FR 3631 UPMC-CNRS, UPMC, Paris, France) [77]. …”

Section: Methodsmentioning

confidence: 99%

Insight into the mechanism of action of temporin-SHa, a new broad-spectrum antiparasitic and antibacterial agent

et al. 2017

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Antimicrobial peptides (AMPs) are promising drugs to kill resistant pathogens. In contrast to bacteria, protozoan parasites, such as Leishmania, were little studied. Therefore, the antiparasitic mechanism of AMPs is still unclear. In this study, we sought to get further insight into this mechanism by focusing our attention on temporin-SHa (SHa), a small broad-spectrum AMP previously shown to be active against Leishmania infantum. To improve activity, we designed analogs of SHa and compared the antibacterial and antiparasitic mechanisms. [K3]SHa emerged as a highly potent compound active against a wide range of bacteria, yeasts/fungi, and trypanosomatids (Leishmania and Trypanosoma), with leishmanicidal intramacrophagic activity and efficiency toward antibiotic-resistant strains of S. aureus and antimony-resistant L. infantum. Multipassage resistance selection demonstrated that temporins-SH, particularly [K3]SHa, are not prone to induce resistance in Escherichia coli. Analysis of the mode of action revealed that bacterial and parasite killing occur through a similar membranolytic mechanism involving rapid membrane permeabilization and depolarization. This was confirmed by high-resolution imaging (atomic force microscopy and field emission gun-scanning electron microscopy). Multiple combined techniques (nuclear magnetic resonance, surface plasmon resonance, differential scanning calorimetry) allowed us to detail peptide-membrane interactions. [K3]SHa was shown to interact selectively with anionic model membranes with a 4-fold higher affinity (KD = 3 x 10−8 M) than SHa. The amphipathic α-helical peptide inserts in-plane in the hydrophobic lipid bilayer and disrupts the acyl chain packing via a detergent-like effect. Interestingly, cellular events, such as mitochondrial membrane depolarization or DNA fragmentation, were observed in L. infantum promastigotes after exposure to SHa and [K3]SHa at concentrations above IC50. Our results indicate that these temporins exert leishmanicidal activity via a primary membranolytic mechanism but can also trigger apoptotis-like death. The many assets demonstrated for [K3]SHa make this small analog an attractive template to develop new antibacterial/antiparasitic drugs.

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Section: Methodsmentioning

confidence: 99%

Insight into the mechanism of action of temporin-SHa, a new broad-spectrum antiparasitic and antibacterial agent

et al. 2017

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“…It has also been realized that the cell wall components of bacteria play important roles in insertion and translocation of AMPs toward cytosolic membrane (33)(34)(35). Several studies have demonstrated higher MICs of AMPs for Gram-negative bacteria compared to Gram-positive organisms (36)(37)(38)(39)(40). In particular, LPS of the outer membrane of Gram-negative bacteria has been found to be actively involved in the mode of action of AMPs (5,(41)(42)(43)(44)(45)(46).…”

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confidence: 99%

Resurrecting Inactive Antimicrobial Peptides from the Lipopolysaccharide Trap

Mohanram

Bhattacharjya

2014

Antimicrob Agents Chemother

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Host defense antimicrobial peptides (AMPs) are a promising source of antibiotics for the treatment of multiple-drug-resistant pathogens. Lipopolysaccharide (LPS), the major component of the outer leaflet of the outer membrane of Gram-negative bacteria, functions as a permeability barrier against a variety of molecules, including AMPs. Further, LPS or endotoxin is the causative agent of sepsis killing 100,000 people per year in the United States alone. LPS can restrict the activity of AMPs inducing aggregations at the outer membrane, as observed for frog AMPs, temporins, and also in model AMPs. Aggregated AMPs, "trapped" by the outer membrane, are unable to traverse the cell wall, causing their inactivation. In this work, we show that these inactive AMPs can overcome LPS-induced aggregations while conjugated with a short LPS binding ␤-boomerang peptide motif and become highly bactericidal. The generated hybrid peptides exhibit activity against Gram-negative and Gram-positive bacteria in high-salt conditions and detoxify endotoxin. Structural and biophysical studies establish the mechanism of action of these peptides in LPS outer membrane. Most importantly, this study provides a new concept for the development of a potent broad-spectrum antibiotic with efficient outer membrane disruption as the mode of action.

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“…However, the generated model had a poor statistical quality ( q 2 = 0.142 and r 2 = 0.787, 14 PCs). Analyzing the complete dataset, we tested the exclusion of two peptides, phylloseptin 3 and phylloseptin 5 due to the uncertainty in their respective IC 50 values, which were reported as >60 μ m and not as 60 μ m , as we initially had considered. A new model was obtained showing better results ( q 2 = 0.561 and r 2 = 0.932, 8 PCs).…”

Section: Resultsmentioning

confidence: 99%

MD simulations and multivariate studies for modeling the antileishmanial activity of peptides

Guerra

Fadel

Baldissera³

et al. 2017

Chem Biol Drug Des

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Leishmaniasis, a protozoan-caused disease, requires alternative treatments with minimized side-effects and less prone to resistance development. Antimicrobial peptides represent a possible choice to be developed. We report on the prospection of structural parameters of 23 helical antimicrobial and leishmanicidal peptides as a tool for modeling and predicting the activity of new peptides. This investigation is based on molecular dynamic simulations (MD) in mimetic membrane environment, as most of these peptides share the feature of interacting with phospholipid bilayers. To overcome the lack of experimental data on peptides' structures, we started simulations from designed 100% α-helices. This procedure was validated through comparisons with NMR data and the determination of the structure of Decoralin-amide. From physicochemical features and MD results, descriptors were raised and statistically related to the minimum inhibitory concentration against Leishmania by the multivariate data analysis technique. This statistical procedure confirmed five descriptors combined by different loadings in five principal components. The leishmanicidal activity depends on peptides' charge, backbone solvation, volume, and solvent-accessible surface area. The generated model possesses good predictability (q = 0.715, r = 0.898) and is indicative for the most and the least active peptides. This is a novel theoretical path for structure-activity studies combining computational methods that identify and prioritize the promising peptide candidates.

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Structure, Antimicrobial Activities and Mode of Interaction with Membranes of Bovel Phylloseptins from the Painted-Belly Leaf Frog, Phyllomedusa sauvagii

Cited by 27 publications

References 40 publications

Insight into the mechanism of action of temporin-SHa, a new broad-spectrum antiparasitic and antibacterial agent

Insight into the mechanism of action of temporin-SHa, a new broad-spectrum antiparasitic and antibacterial agent

Resurrecting Inactive Antimicrobial Peptides from the Lipopolysaccharide Trap

MD simulations and multivariate studies for modeling the antileishmanial activity of peptides

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