Local enhancement of cationic charge density via polyamine side chain incorporation improves the selectivity of antimicrobial peptoids.

Antimicrobial resistance poses a critical threat to global health, necessitating the development of new therapeutics. Peptoids are synthetic analogs of peptides with an N-substituted glycine backbone and have been investigated for antimicrobial therapeutic applications due to their resistance to proteolysis and tunable structures. This study explores antimicrobial peptoids functionalized with polyamine side chains, leveraging the cationic nature of polyamines to enhance interactions with bacterial membranes. A structure-activity relationship (SAR) analysis was conducted to elucidate the influence of polyamine chain length and density on antimicrobial potency and selectivity. The optimized peptoids demonstrated potent activity against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains, while maintaining low cytotoxicity toward mammalian cells. Mechanistic studies demonstrated that these peptoids employ multiple killing mechanisms, including membrane disruption, oxidative damage, and intracellular aggregation of proteins and nucleic acids. This work highlights the potential of polyamine-functionalized peptoids for developing next-generation antimicrobial agents and provides insights into the design principles for enhancing their efficacy and safety.