Design and Development of Self-Assembling Antibacterial Peptide Nanostructures and Functional Materials

Antimicrobial resistance is one of the most pressing threats to global public health. Thus, the development of new antibacterial agents based on unique mechanisms of action and targets represents an urgent unmet medical need.

Antimicrobial and amyloidogenic peptides do not typically share common sequences and normal biological activity. However, a number of antimicrobial peptides have been shown to form amyloid-like structures and well-studied amyloids have been shown to have antimicrobial capabilities. Here, we investigate the interface of antimicrobial and amyloid peptides, which has been studied far less intensively than either type of peptides, to decipher a possible link between both amyloid pathology and antimicrobial activity. Specifically, we have designed and developed minimal peptide-based moieties with antibacterial capabilities based on various biochemical and biophysical characteristics as well as their nano-structure forming capabilities.

We demonstrate the significance of self-assembly to the antibacterial activity of these peptides which are able to completely inhibit bacterial growth and cause significant damage to bacterial morphology, as well as membrane depolarization and permeation. These assays, coupled with the analysis of the upregulation of stress-response two-component systems caused by treatment with the nano-structures demonstrate that treatment with these assemblies leads to significant disruption of the bacterial membrane and consequential bacterial cell death. We have found the peptides to be non-hemolytic and non-cytotoxic towards human cells and have identified their main target as bacterial membrane phospholipids.

In order to address the need for combating nosocomial infections cause by implant failure and wound contamination we have designed and engineered the incorporation of these peptides and nanostructures into tissue scaffolds, which hinder bacterial growth but allow for the proliferation of mammalian cell lines. Thus generating biomedical materials with intrinsic antibacterial qualities.

This work emphasizes the significance of the reciprocation between self-assembly and antimicrobial activity and provides the foundation for a new approach to the design and development of antimicrobial agents and materials.