Antimicrobial Peptides Incorporating Halogenated Marine-Derived Amino Acid Substituents

Small synthetic mimics of cationic antimicrobial peptides represent a promising class of compounds with leads in clinical development for the treatment of persistent microbial infections. The activity and selectivity of these compounds rely on a balance between hydrophobic and cationic components, and here, we explore the activity of 19 linear cationic tripeptides against five different pathogenic bacteria and fungi, including clinical isolates. The compounds incorporated modified hydrophobic amino acids inspired by motifs often found in bioactive marine secondary metabolites in combination with different cationic residues to probe the possibility of generating active compounds with improved safety profiles. Several of the compounds displayed high activity (low mu M concentrations), comparable with the positive controls AMC-109, amoxicillin, and amphotericin B. A higher activity was observed against the fungal strains, and a low in vitro off-target toxicity was observed against erythrocytes and HeLa cells, thereby illustrating effective means for tuning the activity and selectivity of short antimicrobial peptides.

Automated summary

Small synthetic mimics of cationic antimicrobial peptides are promising compounds for treating persistent microbial infections. In this study, we investigated the activity of 19 linear cationic tripeptides against pathogenic bacteria and fungi, including clinical isolates. Modified hydrophobic amino acids inspired by bioactive marine secondary metabolites were used to create compounds with improved safety profiles. Several compounds showed high activity, particularly against fungal strains, with low off-target toxicity to erythrocytes and HeLa cells, indicating effective ways to tune the activity and selectivity of short antimicrobial peptides.