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

Lee Schnaider 1 Sofia Kolusheva 5 Lihi Adler-Abramovich 2 William DeGrado 3 Ehud Gazit 1,4
1Tel Aviv University, Israel
2Tel Aviv University, Israel
3University of California, San Francisco, USA
4Tel Aviv University, Israel
5Ben Gurion University of the Negev, Israel

The rapid growth in number and prevalence of multi-drug resistant bacteria, coupled with a thirty-year discovery void of new antibiotics has brought the world to the brink of a post-antibiotic era. The implications of such an era, in which common infections and minor injuries, which have been treatable for decades, may once again kill, will be devastating. Thus, new antibacterial agents with a reduced tendency for the emergence of resistance represent an urgent unmet medical need.

Antimicrobial and amyloid peptides do not typically share common sequences and normal biological activity. However, a number of antimicrobial peptides have indeed been shown to form amyloid-like β-sheet structures, suggesting antimicrobial peptides have potential self-assembling and amyloidogenic propensities. Furthermore, well-studied amyloids such as amyloid-β, Serum amyloid A and IAPP have been shown to have antimicrobial capabilities. Interestingly, both amyloid and antimicrobial peptides share some common membrane disruption mechanisms by which they target different cells. These common characteristics provide a new paradigm for the design and development of novel antibacterial entities.

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 their structure, stability, amphipathicity, net charge and solubility as well as their nano-structure forming capabilities, predicted membrane interaction propensity and selectivity towards prokaryotic cells.

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 cell wall 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 peptide nano-structures demonstrate that treatment with these assemblies leads to significant disruption of the bacterial membrane and consequential bacterial cell death (Figure 1a). We have found the peptides to be non-hemolytic and non-cytotoxic towards human cells and have identified their main target as bacterial membrane phospholipid groups.

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 cardiac muscle, neuronal and keratinocyte cell lines (Figure 1b-c). Thus generating biomedical materials with intrinsic antibacterial qualities.

Through our reductionist approach we have identified self-assembling single amino acid-based building blocks with notable antimicrobial activity and have incorporated these assemblies in dental sealants, which are routinely used in cavity repair and prevention, to produce enhanced antimicrobial sealants active against the most prominent human dental carry pathogens.

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.

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