Expansion of the antibacterial spectrum of symmetrical amino acid-paired antifungal peptides through structural optimization.

BACKGROUND

Fungal infections often co-occur with antibiotic-resistant bacterial infections, posing clinical treatment challenges. Antimicrobial peptides (AMPs) are considered promising therapeutic alternatives due to their low potential for inducing drug resistance. This study aimed to enhance the antibacterial potency of an existing antifungal peptide through optimization, developing a dual-function peptide targeting both fungal and bacterial pathogens.

METHODS

We designed peptides F1-F4 from the symmetrical amino acid-paired antifungal peptide P19 through threonine (T) substitution and hydrophobic moment (µHrel) adjustment. Then, we assessed their antifungal and antibacterial activities against reference and clinically isolated strains by minimum inhibitory concentrations (MICs), evaluated their toxicity to human red blood cells, and explored the membrane-associated mechanisms.

RESULTS

Peptide F4 was the most promising candidate due to its potent antifungal and antibacterial activities, lack of inhibitory effect on beneficial lactobacilli at concentrations effective against pathogens, and low hemolytic activity. F4 also exhibited strong binding affinity to lipopolysaccharides (LPS) and induced bacterial membrane depolarization and permeabilization.

CONCLUSIONS

Our findings demonstrated that T substitution and hydrophobic moment adjustment effectively enhanced antibacterial activity of the antifungal peptide P19, making peptide F4 a strong candidate for both fungal and bacterial infections.