LAUSR

Antimicrobial polymers (AMPs) have emerged as a promising approach to combat multidrug-resistant pathogens. Developed from binary polymers, which contain cationic and hydrophobic groups, ternary polymers are enhanced by adding neutral hydrophilic monomers to improve their biocompatibility. Cationic groups have attracted significant attention owing to their pivotal role in AMPs. Although many studies have investigated the effect of cationic groups on antimicrobial activity of binary AMPs, there is a lack of comprehensive and systematic evaluation for ternary AMPs. Therefore, a library of 31 statistical amphiphilic ternary polymers containing different cationic groups, including primary amine, guanidine and sulfonium groups was prepared to investigate the impact of cationic groups on antimicrobial activity and biocompatibility. We show that the cationic balance appears to be a critical factor influencing polymers' antibacterial activity and selectivity. Our results reveal that the polymers that have the ratio of the cationic groups ranging between 50-60%, coupled with a cationic/hydrophobic ratio in the range of [1.4-2] and an appropriate neutral hydrophilic/hydrophobic balance, exhibited the highest selectivity toward mammalian cells. Furthermore, selectivity can be improved with suitable cationic moieties and good neutral hydrophilic candidates. In the present study, a lysine-mimicking monomer and PEG chain were the best choices for cationic and hydrophilic sources to develop the most selective AMPs, displaying an impressive selectivity for HC50 and IC50 greater than 83 and 21, respectively. This study elucidates a structure-property-performance relationship for ternary AMPs, which contributes to the development of AMPs capable of selectively targeting gram-negative pathogens. This article is protected by copyright. All rights reserved.