新型抗菌光动力治疗用光敏染料的分子构筑与抗菌活性研究

The emergence of multi-drug resistant bacteria has become a serious threat to human health. The efficiencies of existing anti-infection drugs and therapeutic methods against these strains are very limited. Antimicrobial photodynamic therapy (aPDT) is considered a novel protocol to fight against multi-drug resistant bacteria due to its advantages of broad-spectrum antibacterial property and no drug resistance. At present, the main technique bottleneck limiting the development of aPDT is the lack of cheap but efficient photosensitizers (PSs). In this project, we plan to select benzylidene cycloalknone PSs, which are versatile pharmacophores, have simple molecular structures, easy to be synthesized and modified, and have been proven highly effective in antitumor PDT, as prototype compounds to design novel PSs through introducing a variety of cationic groups and heavy atom groups, altering the species, numbers as well as modification sites of these groups, carry out in vitro and in vivo experiments to evaluate the aPDT efficiency of novel PSs against different multi-drug resistant strains and infectious animal models, study the effect of PSs' structures on their antibacterial mechanisms and activities, and finally explore potential new drugs for aPDT with not only high antibacterial activity but also high selectivity and low cost.

多重耐药菌的出现已经成为严重威胁人类健康的一大隐患，现有的抗感染治疗药物和方法对其疗效都十分有限，抗菌光动力治疗技术具有抗菌谱广、无耐受性等特点，有望成为治疗多重耐药菌感染的新方法。目前，缺乏廉价高效的光敏药物是抗菌光动力治疗技术发展与推广的最大瓶颈。本项目瞄准具有药物结构基础、分子骨架简单、容易合成与修饰、并且已被证实具有良好抗肿瘤光疗效果的亚苄基环烷烃酮类光敏染料，针对抗菌光敏剂需具备的几个关键指标，通过引入多种阳离子基团和重原子基团、调节单个染料分子中所引入基团的数量、种类和修饰位点来构筑新型光敏剂，开展细胞水平与动物水平的抗菌实验，深入研究染料分子构筑方案对其抗菌机理与抗菌效果的影响，为研制出对临床常见多重耐药菌既具有高光动力活性又具有高选择性，同时生产工艺简单、价格相对低廉的新型抗菌光疗药物探索可行性。

本项目的研究目标是通过亚苄基环烷烃酮类光敏剂的分子结构-性能关系研究，揭示不同分子构筑方案对其抗菌光动力（aPDT）活性、选择性以及生物安全性的影响。进一步通过筛选出最佳的光敏剂用于开展细胞水平和动物水平的aPDT研究，为新型光敏药物做基础学术准备。通过本项目的开展，设计、合成并初步评价了23种新型光敏剂对多种耐药菌（包括细菌和真菌）的aPDT性能，筛选出3种光敏剂（P1、P3和Y1）系统开展了对耐氟康唑白念珠菌及其生物膜的aPDT效应研究，进一步选用P3系统开展了对多重耐药铜绿假单胞菌及其生物膜的aPDT效应研究，结果显示光敏剂P3对上述两种多重耐药菌具有高效的aPDT效应。建立了小鼠背部多重耐药菌感染针刺伤口模型并选用光敏剂Y1开展相关实验，结果显示Y1介导的aPDT治疗能够灭活小鼠伤口的耐药菌，阻止皮下化脓继发感染，加速小鼠伤口愈合。初步证实了P3和Y1应用于aPDT的可行性和有效性。上述研究结果已发表学术论文14篇（其中SCI收录7篇，EI收录3篇）；申请中国发明专利4项（其中1项已获授权）。