Unravelling the antimicrobial activity of peptide hydrogel systems: current and future perspectives

Abstract

The use of hydrogels has garnered significant interest as biomaterial and drug delivery platforms for anti-infective applications. For decades antimicrobial peptides have been heralded as a much needed new class of antimicrobial drugs. Self-assembling peptide hydrogels with inherent antimicrobial ability have recently come to the fore. However, their fundamental antimicrobial properties, selectivity and mechanism of action are relatively undefined. This review attempts to establish a link between antimicrobial efficacy; the self-assembly process; peptide-membrane interactions and mechanical properties by studying several reported peptide systems: β-hairpin/β-loop peptides; multidomain peptides; amphiphilic surfactant-like peptides and ultrashort/low molecular weight peptides. We also explore their role in the formation of amyloid plaques and the potential for an infection etiology in diseases such as Alzheimer's. We look briefly at innovative methods of gel characterization. These may provide useful tools for future studies within this increasingly important field.

Fig. 1. (a) Examples of the various nanostructures which may be formed during self-assembly. (b) The self-assembly process of gelation. The peptide gelators (blue ovals) self-assemble into secondary structures, commonly β-sheet and α-helical, when a trigger is applied that makes the gelators insoluble. Secondary structures can either be held together by intermolecular forces of attraction or covalent bonds. These secondary structures entangle to immobilize water which forms a gel.

Fig. 2. The various modes of action proposed for antimicrobial peptides' effect on bacterial cell membranes including barrel-stave, toroidal pore or carpet model, as well as less disruptive non-pore mechanisms. The mechanism of bilayer perturbation is dependent on the peptide and the lipid membrane composition, and may change depending on peptide concentration, temperature and pH.

Fig. 3. Examples of peptide hydrogel systems (ai) mechanism of folding and self-assembly for MAX1 β-hairpin hydrogel formation. Resulting gels are self-supporting as image at far right shows. (aii) Sequence of MAX1 β-hairpin. Adapted with permission from ref. . Copyright (2007) American Chemical Society. (b) Chemical Structures of the lipids and surfactant like peptides used to form the vesicle shown. Adapted with permission from ref. . Copyright (2018) American Chemical Society. (c) Chemical structure of an ultrashort peptide composed of a naphthalene (Nap) protecting group and a diphenylalanine (FF) peptide chain. (d) Colour-coded chemical structure of a multidomain peptide that can be designed to contain variable numbers of lysine residues and (QL) repeating units for the investigation of both molecular and supramolecular structure-dependent cytotoxicity and antimicrobial activity. Red: leucine; green: glutamine; grey: lysine. Adapted from with permission from ref. , The Royal Society of Chemistry.

Fig. 4. The suggested modes of antimicrobial action of amyloid-β peptides.

Fig. 5. Characterization techniques used to measure self-assembly and gel properties and their functional length scales.

Emily R. Cross

Sophie M. Coulter

Sreekanth Pentlavalli

Garry Laverty