Synthetic mimics of antimicrobial peptides based on poly(diitaconamide): synthesis, bioactivity and stability.

Abstract

Synthetic mimics of antimicrobial peptides (SMAMPs) have emerged as a promising alternative to conventional antibiotics in the fight against antimicrobial resistance. Here, a new class of poly(diitaconamide)-based SMAMPs featuring facially amphiphilic repeat units is presented. Copolymers with systematically varied hydrophobicity and charge density are obtained by free radical copolymerization combining diitaconamide and acrylamide-based repeat units, each bearing different alkyl substituents. These polymers have good hydrolytic stability over a wide pH range. They exhibit structure-bioactivity relationships typical for facially amphiphilic antimicrobial polymers, including selectivity for bacteria over mammalian cells: increasing the hydrophobicity enhances the antimicrobial activity, particularly against Escherichia coli bacteria, but also leads to increased haemolytic activity. Copolymers with pentyl-substituted co-repeat units display overall higher antimicrobial activity, whereas their propyl-substituted analogues exhibit improved selectivity towards bacterial cells over mammalian cells. These trends are consistent with previously reported facially amphiphilic SMAMP systems. They indicate that the facial amphiphilicity design concept was successfully translated to this polymer type and highlight the critical role of balanced amphiphilicity on the repeat unit level. Interestingly, one of the poly(diitaconamide) SMAMPs is selective for Gram-negative over Gram-positive bacteria, and the combination of precise hydrophobic balance and suitable molar mass is proposed as a tool to achieve such Gram-selectivity. As a demonstrator for clinical applications, SMAMP ointments with high antimicrobial activity and a pot stability of at least 8 weeks are presented, which are also selective for Gram-negative over Gram-positive bacteria.