Department of pharmacy, The Fourth Military Medical University, Changlexilu 169, Xi'an city, China.
Biomater Sci. 2019 Mar 26;7(4):1399-1410. doi: 10.1039/c8bm00990b.
With the increase in antibiotic resistance, the development of new antibacterial agents is urgent. Photosensitizers with no detectable resistance are promising antibacterial agents. However, most photosensitizers are insoluble, structurally unstable and ineffective against Gram-negative bacteria due to their negatively charged cell wall that hinder their use. In this study, a novel bacteria-activated photosensitizer ionic liquid was designed and assembled to improve the solubility, stability and antibacterial ability of photodynamic therapy. The cation 1-vinyl-3-dodecyl imidazole has been designed, which has strong binding energy with the major constituent of the cell wall. The anion selected was chlorin e6 (Ce6) since it could respond to the acidic microenvironment of bacterial infection. The Ce6 ionic liquid (Ce6-IL) composed of 1-vinyl-3-dodecyl imidazole and Ce6 not only exhibited bacteria-activated ability because its cation could firmly bond with peptidoglycan in the cell wall, but also had excellent acid responsive ability due to the protonation reaction of COO- in its anion. The binding energy of the cation with peptidoglycan was calculated via molecular dynamics simulation, and the pH-responsive behavior of Ce6-IL was verified via HR-MS. The surface potential, mechanical property, morphology and uptake rate results indicated that the cation could destroy the cell wall and promote the anion Ce6 to enter the bacteria. Due to the dual-mode antibacterial action of its cation and anion, Ce6-IL was more effective against Gram-negative and Gram-positive bacteria than Ce6 alone and had wide-spectrum antibacterial ability. The in vitro studies showed that the IC50 of Ce6-IL against E. coli and S. aureus was reduced by 100 and 10 times, respectively. Furthermore, the in vivo studies indicated that Ce6-IL was more effective for eliminating bacterial infection and could accelerate wound healing. The compatibility test showed that Ce6-IL had low toxicity and exhibited excellent biocompatibility.
随着抗生素耐药性的增加，开发新的抗菌剂迫在眉睫。无耐药性的光敏剂是很有前途的抗菌剂。然而，由于其带负电荷的细胞壁阻碍了它们的使用，大多数光敏剂溶解度低、结构不稳定且对革兰氏阴性菌无效。在这项研究中，设计并组装了一种新型细菌激活光敏剂离子液体，以提高光动力疗法的溶解度、稳定性和抗菌能力。阳离子 1-乙烯基-3-十二烷基咪唑已被设计出来，它与细胞壁的主要成分具有很强的结合能。选择的阴离子是叶绿素 e6（Ce6），因为它可以响应细菌感染的酸性微环境。由 1-乙烯基-3-十二烷基咪唑和 Ce6 组成的 Ce6 离子液体（Ce6-IL）不仅具有细菌激活能力，因为其阳离子可以与细胞壁中的肽聚糖牢固结合，而且由于其阴离子中的 COO-发生质子化反应，还具有优异的酸响应能力。通过分子动力学模拟计算了阳离子与肽聚糖的结合能，并通过 HR-MS 验证了 Ce6-IL 的 pH 响应行为。表面电势、力学性能、形态和摄取率结果表明，阳离子可以破坏细胞壁并促进阴离子 Ce6 进入细菌。由于其阳离子和阴离子的双重模式抗菌作用，Ce6-IL 对革兰氏阴性菌和革兰氏阳性菌的抗菌效果均优于 Ce6 单独使用，具有广谱抗菌能力。体外研究表明，Ce6-IL 对大肠杆菌和金黄色葡萄球菌的 IC50 分别降低了 100 倍和 10 倍。此外，体内研究表明，Ce6-IL 更有效地消除细菌感染并能加速伤口愈合。相容性试验表明，Ce6-IL 毒性低，具有良好的生物相容性。
