Bacteria-activated chlorin e6 ionic liquid based on cation and anion dual-mode antibacterial action for enhanced photodynamic efficacy
Bacteria-activated chlorin e6 ionic liquid based on cation and anion dual-mode antibacterial action for enhanced photodynamic efficacy
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基于阳离子和阴离子双模式抗菌作用的细菌激活二氢卟酚e6离子液体，增强光动力功效
DOI：
10.1039/c8bm00990b
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发表时间：
2019
影响因子：
6.6
通讯作者：
Wu Hong
中科院分区：
文献类型：
--
作者：
Wang Chaoli;Chen Peng;Qiao Youbei;Kang Yuan;Guo Songyan;Wu Danfeng;Wang Jian;Wu Hong
随着抗生素耐药性的增加，开发新的抗菌药物迫在眉睫。未检测到耐药性的光敏剂是有前途的抗菌剂。然而，大多数光敏剂是不溶性的，结构不稳定的，并且由于它们的带负电荷的细胞壁而对革兰氏阴性菌无效，这阻碍了它们的使用。为了提高光动力治疗的溶解性、稳定性和抗菌能力，设计并组装了一种新型的细菌活化光敏剂离子液体。设计了1-乙烯基-3-十二烷基咪唑阳离子，它与细胞壁的主要成分有很强的结合能。选择的阴离子是二氢卟啉e6（Ce 6），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Ce 6组成的Ce 6离子液体（Ce 6-IL）不仅由于其阳离子能与细胞壁中的肽聚糖牢固地结合而具有细菌活化能力，而且由于其阴离子中的COO-发生质子化反应而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，并通过高分辨质谱（HR-MS）验证了Ce 6-IL的pH响应行为，表面电位、力学性能、形貌和摄取率的结果表明，阳离子能够破坏细胞壁，促进阴离子Ce 6进入细菌。由于Ce 6-IL具有阴、阳离子双模式抗菌作用，因此Ce 6-IL对革兰氏阴性菌和革兰氏阳性菌的抑菌效果均优于Ce 6单用，且具有广谱抗菌能力。体外实验结果表明，Ce 6-IL对大肠杆菌的IC 50为0。coli和革兰氏阳性菌S.金黄色葡萄球菌分别减少了100和10倍。体内实验结果表明，Ce 6-IL具有较好的清除细菌感染和促进伤口愈合的作用。相容性试验表明，Ce 6-IL毒性低，具有良好的生物相容性。
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.