Self-assembling dipeptide antibacterial nanostructures with membrane disrupting activity

Darya Bychenko,Lee Schnaider,Lihi Adler-Abramovich,Ehud Gazit,Bruk Mensa,Sayanti Brahmachari,Linda J W Shimon,Sofiya Kolusheva,William F Degrado,Nathan W Schmidt,Shira Shaham-Niv

doi:10.1038/s41467-017-01447-x

Abstract

Peptide-based supramolecular assemblies are a promising class of nanomaterials with important biomedical applications, specifically in drug delivery and tissue regeneration. However, the intrinsic antibacterial capabilities of these assemblies have been largely overlooked. The recent identification of common characteristics shared by antibacterial and self-assembling peptides provides a paradigm shift towards development of antibacterial agents. Here we present the antibacterial activity of self-assembled diphenylalanine, which emerges as the minimal model for antibacterial supramolecular polymers. The diphenylalanine nano-assemblies completely inhibit bacterial growth, trigger upregulation of stress-response regulons, induce substantial disruption to bacterial morphology, and cause membrane permeation and depolarization. We demonstrate the specificity of these membrane interactions and the development of antibacterial materials by integration of the peptide assemblies into tissue scaffolds. This study provides important insights into the significance of the interplay between self-assembly and antimicrobial activity and establishes innovative design principles toward the development of antimicrobial agents and materials.

Highlights

Peptide-based supramolecular assemblies are a promising class of nanomaterials with important biomedical applications, in drug delivery and tissue regeneration
An important step in this direction was made by Ghadiri and coworkers in their design of cyclic hexa- and octa-D,L-alpha peptides, which assembled into tubular structures mimicking the facially amphipathic nature of natural antimicrobial peptides and displayed antibacterial activity[48]
In order to gain a better understanding of the significance of self-assembly to antibacterial activity, assembled diphenylalanine (FF), as well as diglycine (GG), a dipeptide that does not self-assemble, and non-assembled diphenylalanine, which consists of diphenylalanine at sub-critical concentrations, were examined

Summary

Introduction

Peptide-based supramolecular assemblies are a promising class of nanomaterials with important biomedical applications, in drug delivery and tissue regeneration. Additional members of the immune system, such as the mitochondrial antiviral signaling protein (MAVS), have been shown to undergo conformational changes and form amyloid-like structures that enable them to carry out their activity[25] These structures closely resemble classical amyloidogenic assemblies, which are exceptionally stable unbranched, fibrillar, cross β-sheet quaternary protein, and polypeptide structures[26,27] that attain their stability through noncovalent interactions, including hydrogen bonds, hydrophobic interactions, and π–π stacking interactions[28]. Given the differences between canonical antimicrobial peptides and the diphenylalanine nanostructures, a comprehensive inquiry into the mechanism of action of the later agents was carried out, providing important insights into the significance of the interplay between self-assembly and antimicrobial activity. The minimal nature of this model makes it an attractive platform for the development of alternative antimicrobial therapeutics due to the extensive possibilities for its chemical modifications and allows for further examination of fundamental questions concerning the mechanism of action of self-assembling antimicrobial peptides

Methods

Results

Conclusion