Synthesis of Antibacterial Glycosylated Polycaprolactones Bearing Imidazoliums with Reduced Hemolytic Activity

Most synthetic antimicrobial polymers are not biodegradable, thus limiting their potential for large-scale applications in personal care disinfection and environmental contaminations. Poly(epsilon-caprolactone) (PCL) is known to be both biodegradable and biocompatible, thus representing an ideal candidate biopolymer for antimicrobial applications. Here we successfully grafted alkylimidazolium (Im) onto PCL to mimic the cationic properties of antimicrobial peptides. The poly(epsilon-caprolactone)-graft-butylimidazolium had only moderate MICs (32 mu g/mL), reasonably good red blood cell selectivity (36) and relatively good fibroblast compatibility (81% cell viability at 100 mu g/mL), indicating that combining the hydrophobic PCL backbone with the most hydrophilic butylimidazolium gives a good balance of MIC and cytotoxicity. On the other hand, the PCL-graft-hexylimidazolium and -octylimidazolium demonstrated better MICs (4-32 mu g/mL), but considerably worse cytotoxicity. We postulated that the worse hydrophilicity of hexylimidazolium and octylimidazolium was responsible for their higher cytotoxicity and sought to moderate their cytotoxicity with different sugar compositions and lengths. Through our screening, we identified a candidate polymer, P(C6Im)(0.35)CL-co-P(Man)(0.65)CL, that demonstrated both superior MIC and very low cytotoxicity. We further demonstrated that our biopolymer hit had superior antimicrobial kinetics compared to the antibiotic vancomycin. This work paves the way forward for the use of biodegradable polyesters as the backbone scaffold for biocompatible antibacterial agents, by clicking with different types and ratios of alkylimidazolium and carbohydrate moieties.