Peptide Self-Assembly Is Linked to Antibacterial, but Not Antifungal, Activity of Histatin 5 Derivatives

Abstract

The rise of multidrug-resistant pathogens has awakened interest in new drug candidates such as antimicrobial peptides and their derivatives. Recent work suggests that some antimicrobial peptides have the ability to self-assemble into ordered amyloid-like nanostructures which facilitate their antibacterial activity. Here, we evaluate a histatin-based antimicrobial peptide, and its self-assembling derivative, in the interplay between self-assembly, membrane interactions, and antibacterial and antifungal activities. We demonstrate substantial membrane targeting by both peptides, as well as mechanistic insights into this mode of action, which correlates to their antifungal activity and is not affected by their self-assembling state. The ability to self-assemble does, however, significantly affect peptide antibacterial activity against both Gram-negative and Gram-positive bacteria. These results are surprising and hint at important distinctions between antifungal and antibacterial peptide activities in prokaryotes and eukaryotic microbes. IMPORTANCE Antimicrobial peptides are important modulators of host defense against bacterial, fungal, and viral pathogens in humans and other multicellular organisms. Two converging paradigms point to a link between antimicrobial peptides that self-assemble into amyloid-like nanoassemblies and classical amyloidogenic peptides that often have potent broad-spectrum antimicrobial activity, suggesting that antimicrobial and amyloidogenic peptides may represent two sides of the same coin. Here, we asked if the ability of an antifungal peptide to self-assemble affects its antifungal or antibacterial activity. We found that modifications of classical antifungal peptide derivative allowed it to self-assemble and did not alter its antifungal activity, and yet self-assembly substantially increased the antibacterial activity of the peptide. These results support the idea that peptide self-assembly can enhance antibacterial activities and emphasize a distinction between the action of antifungal peptides and that of antibacterial peptides. Accordingly, we suggest that the possible generality of this distinction should be widely tested.

Antimicrobial peptides: mechanism of action, activity and clinical potential

“…AMPs have the ability to self-assemble into an ordered amyloid-like nanostructures which facilitate their antibacterial activity by achieving more specific and stronger interactions with microbial membranes [ 342 ]. Nanomaterials can effectively kill bacteria by destroying bacterial cell membrane and causing intracellular material leakage.…”

Fabrication of Supramolecular Antibacterial Nanofibers with Membrane-Disruptive Mechanism

“…In a study of the interaction between the self-assembled nanopeptide PTP-7b and cells, Chen and coworkers noted that the self-assembly ability of the peptide was as important to the antibacterial effect as the number of charges and secondary structure . The derivative peptide LF7 exhibited the ability to self-assemble after modification of antifungal peptides, significantly improving the antibacterial ability without changing the antifungal activity . These studies provide important insights into the addition of self-assembly to the design of AMPs and the relationship between the self-assembly and the biological activity of AMPs, laying the foundation for the emerging field of AMPs design.…”

“…22 The derivative peptide LF7 exhibited the ability to self-assemble after modification of antifungal peptides, significantly improving the antibacterial ability without changing the antifungal activity. 23 These studies provide important insights into the addition of self-assembly to the design of AMPs and the relationship between the self-assembly and the biological activity of AMPs, laying the foundation for the emerging field of AMPs design.…”

Design Methods for Antimicrobial Peptides with Improved Performance

“…Self-assembling AMPs display several advantages, such as biocompatibility, improved stability in diverse physiological conditions, lower toxicity, high resistance to proteolytic degradation, and improved antimicrobial activity ( Whitesides & Boncheva, 2002 ; Ye et al, 2019 ; Yu et al, 2016 ). For example, the self-assembled AMP dhvar2 (KRLFKELLFSLRKY), a derivative of histatin 5, exhibited improved antibacterial activity compared to its parent peptide ( Schnaider et al, 2020 ). Furthermore, the self-assembly of supramolecules of human α-defensin 5 through myristylation of the C-terminal can significantly improve its microbicidal activity against MRSA and E. coli , with minimal toxicity or hemolytic activity than non-assembling analogs ( Lei et al, 2018 ).…”