Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge, CB3 0AS, UK.
Sci Rep. 2022 Apr 21;12(1):6580. doi: 10.1038/s41598-022-10394-7.
The development of effective pathogen reduction strategies is required due to the rise in antibiotic-resistant bacteria and zoonotic viral pandemics. Photodynamic inactivation (PDI) of bacteria and viruses is a potent reduction strategy that bypasses typical resistance mechanisms. Naturally occurring riboflavin has been widely used in PDI applications due to efficient light-induced reactive oxygen species (ROS) release. By rational design of its core structure to alter (photo)physical properties, we obtained derivatives capable of outperforming riboflavin's visible light-induced PDI against E. coli and a SARS-CoV-2 surrogate, revealing functional group dependency for each pathogen. Bacterial PDI was influenced mainly by guanidino substitution, whereas viral PDI increased through bromination of the flavin. These observations were related to enhanced uptake and ROS-specific nucleic acid cleavage mechanisms. Trends in the derivatives' toxicity towards human fibroblast cells were also investigated to assess viable therapeutic derivatives and help guide further design of PDI agents to combat pathogenic organisms.
由于抗生素耐药细菌和人畜共患病毒大流行的出现，需要开发有效的病原体减少策略。光动力灭活（PDI）细菌和病毒是一种有效的减少策略，它绕过了典型的耐药机制。由于能够有效地释放光诱导的活性氧（ROS），天然存在的核黄素已广泛用于 PDI 应用。通过对其核心结构进行合理设计来改变（光）物理性质，我们获得了能够超越核黄素可见光诱导的针对大肠杆菌和 SARS-CoV-2 替代物的 PDI 作用的衍生物，揭示了每种病原体对功能基团的依赖性。细菌 PDI 主要受胍基取代的影响，而病毒 PDI 则通过黄素的溴化来增加。这些观察结果与增强的摄取和 ROS 特异性核酸切割机制有关。还研究了衍生物对人成纤维细胞的毒性趋势，以评估可行的治疗性衍生物，并帮助指导进一步设计 PDI 剂以对抗致病生物。
