Influence of the Nature of the Cationic Residues on the Activity of the Antimicrobial Peptides of the Lynronne Family

Abstract

Most antimicrobial peptides (AMPs) are cationic, with positively charged amino acid residues (i.e., arginine, lysine, and/or histidine) being responsible for their selective interaction with bacteria. In the present study, we investigated the influence of the nature of cationic residues taking the Lynronnes peptides as models. Derivatives were designed and synthetized with substitutions of the type of cationic residues present. All derivatives and parental peptides were studied in terms of secondary structure, antimicrobial activity, anti-biofilm activity, mechanism of action, and in vitro toxicity. All-His peptides were found inactive, whereas all-Lys variants showed the highest potency against Gram-negative strains, particularly against E. coli. All-Arg analogues were more active against Gram-positive strains with enhanced stability under salt or serum conditions but were also more hemolytic. Mechanistic studies revealed that the peptides act by membrane permeabilization. Finally, Lynronne-3 and its all-Lys derivative proved the most effective in both the prevention and eradication of biofilms. These findings confirm that the type of cationic residue present in AMPs affects their activity, toxicity, and sensitivity to host factors, with different effects depending on the rest of the amino acid sequence, Lys-substitution emerging as a promising strategy in the case of Lynronnes for targeting E. coli.