Probing the relationships between self-assembly and the antimicrobial activity of amyloidogenic peptides: The islet...

Antimicrobial peptides (AMPs) are key components of the innate immune system across diverse organisms. Interestingly, some AMPs can adopt β-sheet secondary structure and self-assemble into amyloid-like fibrils. Recent works have also revealed that amyloidogenic peptides exhibit antimicrobial properties and share a common mechanism of plasma membrane perturbation with AMPs. In this study, we explored the relationships between the antimicrobial activity of amyloidogenic peptides and their self-assembly by using the islet amyloid polypeptide (IAPP) as a model. IAPP is an aggregation-prone 37-residue hormone whose pancreatic deposition and accumulation are associated with type II diabetes. Antimicrobial assays revealed that IAPP monomers and prefibrillar aggregates, including soluble oligomers, inhibit the growth of Escherichia coli and Staphylococcus epidermidis. Additionally, monomeric and prefibrillar proteospecies perturbed anionic lipid vesicles that mimic bacterial plasma membrane and decrease the metabolic activity. In contrast, pre-assembled amyloid fibrils exhibited weak antimicrobial activities and lipid membrane perturbation, although they agglutinated bacteria avidly. By taking advantage of residue-specific substitutions that modulate the aggregation propensity, we observed that derivatives with hindered amyloidogenicity retained antimicrobial activities, while those with accelerated kinetics of amyloid self-assembly had weaker antimicrobial effect. Moreover, by modulating the propensity of IAPP to fold into an α-helix, we observed that amyloid formation is not a prerequisite for the antimicrobial activity, while the destabilization of helical folding reduced IAPP antimicrobial activity. This study provides fundamental mechanistic insights of the modest antimicrobial activity of IAPP and highlights that precaution should be taken before generalizing the antimicrobial potential of self-assembling amyloid polypeptides.