Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences , Nanyang Technological University , 21 Nanyang Link , Singapore 637371 , Republic of Singapore.
School of Chemical and Biomedical Engineering , Nanyang Technological University , 62 Nanyang Drive , Singapore 637459 , Republic of Singapore.
Biomacromolecules. 2019 Feb 11;20(2):949-958. doi: 10.1021/acs.biomac.8b01577. Epub 2019 Jan 10.
Most synthetic antimicrobial polymers are not biodegradable, thus limiting their potential for large-scale applications in personal care disinfection and environmental contaminations. Poly(ε-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(ε-caprolactone)- graft-butylimidazolium had only moderate MICs (32 μg/mL), reasonably good red blood cell selectivity (36) and relatively good fibroblast compatibility (81% cell viability at 100 μg/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 μg/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)CL- co-P(Man)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.
大多数合成的抗菌聚合物不可生物降解，因此限制了它们在个人护理消毒和环境污染等大规模应用中的潜力。聚己内酯（PCL）已知具有生物降解性和生物相容性，因此是抗菌应用的理想候选生物聚合物。在这里，我们成功地将烷基咪唑鎓（Im）接枝到 PCL 上，模拟抗菌肽的阳离子特性。聚（ε-己内酯）-接枝-丁基咪唑鎓的 MIC 仅为中等（32 μg/mL），对红细胞具有较好的选择性（36）和相对较好的成纤维细胞相容性（100 μg/mL 时细胞活力为 81%），表明将疏水性 PCL 主链与最亲水性的丁基咪唑鎓结合可很好地平衡 MIC 和细胞毒性。另一方面，PCL-接枝-己基咪唑鎓和-辛基咪唑鎓表现出更好的 MIC（4-32 μg/mL），但细胞毒性却差得多。我们推测，己基咪唑鎓和辛基咪唑鎓较差的亲水性是其细胞毒性较高的原因，并试图通过不同的糖组成和长度来调节其细胞毒性。通过筛选，我们确定了一种候选聚合物 P(C6Im)CL-co-P(Man)CL，该聚合物具有较高的 MIC 和非常低的细胞毒性。我们进一步证明，我们的生物聚合物比抗生素万古霉素具有更好的抗菌动力学。这项工作为使用可生物降解的聚酯作为生物相容性抗菌剂的骨架支架铺平了道路，通过与不同类型和比例的烷基咪唑鎓和碳水化合物片段进行点击反应。
