Effect of minimal structural modifications on the membrane interaction of short antimicrobial peptides: An experimental and computational study

Antimicrobial resistance demands innovative strategies to tackle bacterial infections. This study reports the synthesis of short antimicrobial peptides with minimal structural modifications, aiming at enhancing efficacy and reducing toxicity. Thus, sixteen derivatives were synthesized via solid-phase peptide synthesis (SPPS) and their antibacterial, cytotoxic, and hemolytic activities were evaluated. Most compounds effectively inhibited the growth of S. aureus and P. aeruginosa, including both commercial and clinically isolated bacterial strains. Structural modifications, including halogens or bulky alkylic substitutions and amino acid replacement, improved membrane interactions and activity. Molecular dynamics simulations highlighted the role of amphipathic configurations and π-π interactions in facilitating bacterial membrane penetration. Results underline the potential of newly synthesized derivatives as promising candidates against drug-resistant bacteria.