Enhancing Antimicrobial Peptide Potency through Multivalent Presentation on Coiled-Coil Nanofibrils

Abstract

Antibiotic-resistant microbes have become a global health threat. New delivery systems that enhance the efficacy of antibiotics and/or overcome the resistances can help combat them. In this context, we present FF03, a fibril-forming α-helical coiled-coil peptide that functions as an efficient scaffold for the multivalent presentation of the weakly cationic antimicrobial peptide (AMP) IN4. The resulting IN4-decorated FF03 coiled-coil fibrils (FF03 + IN4) are nonhemolytic and noncytotoxic and show enhanced antimicrobial activity relative to unconjugated IN4 and standard antibiotics against several bacterial strains. Scanning electron microscopy analysis shows that FF03 + IN4 nanofibers disrupt methicillin-resistant Staphylococcus aureus membranes, indicating a surface-level mode of action. Furthermore, transmission electron microscopy and circular dichroism studies indicate that decoration of the FF03 scaffold with IN4 does not alter the secondary-structure propensity or fibril-forming properties of FF03. Thus, the approach reported herein provides a new peptidic scaffold for the multivalent presentation of AMPs to obtain nonhemolytic and noncytotoxic antimicrobial systems with improved efficacy relative to the unconjugated AMP analogues.

Lipidation of Naturally Occurring α-Helical Antimicrobial Peptides as a Promising Strategy for Drug Design

“…The C 10 -ATRA-1 analogue were also found to adopt a coiled-coil structure in the presence of the artificial lipid membranes. It is believed that the peptides folded in this way can be characterized by lower cytotoxicity [ 64 ].…”

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

“…60 Recently Thota and colleagues demonstrated that the efficacy of a weak cationic antimicrobial peptide (IN4) could be improved by attaching it to a fibril-forming α-helical coiled-coil peptide (FF03). 86 Hydrogel formation was not observed but the fibrous scaffold enhanced the presentation of cationic peptide to bacterial membranes with improved efficacy relative to the unconjugated AMP analogues and reduced toxicity to mammalian cells. The cationic charge density was more readily accessible to interact with anionic bacterial cell membranes via stronger electrostatic interactions.…”

Histidine-Containing Amphiphilic Peptide-Based Non-Cytotoxic Hydrogelator with Antibacterial Activity and Sustainable Drug Release

“…In recent years, peptide-based hydrogels , have been developed as biomaterials that act as antimicrobial agents for the treatment of infectious diseases . Several kinds of hydrogels have been reported so far, , but there are few peptide-based low molecular weight hydrogels that inherently show antimicrobial activity. − Polycation moieties have antimicrobial properties, but often show a certain level of toxicity to mammalian cells .…”

“…In recent years, this property has been explored to make injectable hydrogels that can be used in localized therapy in a particular tissue. 36 In recent years, peptide-based hydrogels 37,38 have been developed as biomaterials that act as antimicrobial agents 39 for the treatment of infectious diseases. 40 Several kinds of hydrogels have been reported so far, 41,42 but there are few peptide-based low molecular weight hydrogels that inherently show antimicrobial activity.…”