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Morphing of Amphipathic Helices to Explore the Activity and Selectivity of Membranolytic Antimicrobial Peptides.

ABSTRACT: Naturally occurring membranolytic antimicrobial peptides (AMPs) are rarely cell-type selective and highly potent at the same time. Template-based peptide design can be used to generate AMPs with improved properties de novo. Following this approach, 18 linear peptides were obtained by computationally morphing the natural AMP Aurein 2.2d2 GLFDIVKKVVGALG into the synthetic model AMP KLLKLLKKLLKLLK. Eleven of the 18 chimeric designs inhibited the growth of Staphylococcus aureus, and six peptides were tested and found to be active against one resistant pathogenic strain or more. One of the peptides was broadly active against bacterial and fungal pathogens without exhibiting toxicity to certain human cell lines. Solution nuclear magnetic resonance and molecular dynamics simulation suggested an oblique-oriented membrane insertion mechanism of this helical de novo peptide. Temperature-resolved circular dichroism spectroscopy pointed to conformational flexibility as an essential feature of cell-type selective AMPs.

SUBMITTER: Muller AT

PROVIDER: S-EPMC7547863 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Morphing of Amphipathic Helices to Explore the Activity and Selectivity of Membranolytic Antimicrobial Peptides.

Müller Alex T AT Posselt Gernot G Gabernet Gisela G Neuhaus Claudia C Bachler Simon S Blatter Markus M Pfeiffer Bernhard B Hiss Jan A JA Dittrich Petra S PS Altmann Karl-Heinz KH Wessler Silja S Schneider Gisbert G

Biochemistry 20200916 39

Naturally occurring membranolytic antimicrobial peptides (AMPs) are rarely cell-type selective and highly potent at the same time. Template-based peptide design can be used to generate AMPs with improved properties <i>de novo</i>. Following this approach, 18 linear peptides were obtained by computationally morphing the natural AMP Aurein 2.2d2 GLFDIVKKVVGALG into the synthetic model AMP KLLKLLKKLLKLLK. Eleven of the 18 chimeric designs inhibited the growth of <i>Staphylococcus aureus</i>, and si ...[more]

PMID: 32936629

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Project description:The evolution of bonded restorations has undergone great progress over several decades. Nonetheless, life spans of bonded restorations are limited mainly because of the eventual incidence of recurrent caries. Over time, water and waterborne agents (acids, enzymes) degrade the components of the dentin/restoration interface, allowing bacterial colonization and dentin reinfection at the margins of the restoration. We developed a 2-tier protective technology consisting of priming/coating dentin with amphipathic and antimicrobial peptides (AAMPs) to obtain hydrophobic/water-repellent and antibiofilm dentin-resisting recurrent caries around bonded restorations. We tested a series of AAMPs to assess their structure-function relationships as well as the effects of different dentin-conditioning methods on the structural features of AAMP-coated dentin. We found relation between the secondary structure of AAMPs (high portion of β-sheet), the antimicrobial potency of AAMPs, and the AAMPs' ability to form hydrophobic coatings on dentin. We also determined that AAMPs had preferential adsorption on the mineral phase of dentin, which suggested that peptides arrange their cationic and hydrophilic motifs in direct contact with the negatively charged minerals in the hydrophilic dentin. These results led us to explore different dentin-conditioning methods that would increase the mineral/collagen ratio and their effect on AAMP immobilization. We innovatively imaged the spatial distribution of the AAMPs in relation to the dentinal tubules and collagen network using a minimally invasive multimodal imaging technique: multiphoton-second harmonic generation. Using multiphoton-second harmonic generation imaging, we determined that partial deproteinization of dentin increased the amount of immobilized AAMPs as compared with the total etched dentin at the dentin surface and extended deeply around dentinal tubules. Last, we analyzed the release rate of AAMPs from dentin coatings in artificial saliva to predict their stability in the clinical setting. In conclusion, priming dentin with AAMPs is a versatile new approach with potential to fortify the otherwise vulnerable adhesive-based interfaces.

Dataset Information

Morphing of Amphipathic Helices to Explore the Activity and Selectivity of Membranolytic Antimicrobial Peptides.

Publications

Morphing of Amphipathic Helices to Explore the Activity and Selectivity of Membranolytic Antimicrobial Peptides.

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