AbstractIn addition to the discovery of new (modified) potent antibiotics to combat antibiotic resistance, there is a critical need to develop novel strategies that would restrict their off‐target effects and unnecessary exposure to bacteria in our body and environment. We report a set of new photoswitchable arylazopyrazole‐modified norfloxacin antibiotics that present a high degree of bidirectional photoisomerization, impressive fatigue resistance and reasonably high cis half‐lives. The irradiated isomers of most compounds were found to exhibit nearly equal or higher antibacterial activity than norfloxacin against Gram‐positive bacteria. Notably, against norfloxacin‐resistant S. aureus bacteria, the visible‐light‐responsive p‐SMe‐substituted derivative showed remarkably high antimicrobial potency (MIC of 0.25 μg/mL) in the irradiated state, while the potency was reduced by 24‐fold in case of its non‐irradiated state. The activity was estimated to be retained for more than 7 hours. This is the first report to demonstrate direct photochemical control of the growth of antibiotic‐resistant bacteria and to show the highest activity difference between irradiated and non‐irradiated states of a photoswitchable antibiotic. Additionally, both isomers were found to be non‐harmful to human cells. Molecular modellings were performed to identify the underlying reason behind the high‐affinity binding of the irradiated isomer to topoisomerase IV enzyme.
摘要 除了发现新的(改良的)强效抗生素来对抗抗生素耐药性之外,我们还迫切需要开发新的策略来限制抗生素的脱靶效应以及在人体和环境中与细菌不必要的接触。我们报告了一组新的可光开关芳基
吡唑修饰的
诺氟沙星抗生素,它们具有高度的双向光异构化、令人印象深刻的抗疲劳性和相当高的顺式半衰期。研究发现,大多数化合物的辐照异构体对革兰氏阳性菌的抗菌活性几乎与
诺氟沙星相同或更高。值得注意的是,针对耐
诺氟沙星的
金黄色葡萄球菌,可见光响应的 p-SMe 取代衍
生物在辐照状态下显示出极高的抗菌效力(MIC 为 0.25 μg/mL),而在非辐照状态下,效力降低了 24 倍。据估计,其活性可保持 7 小时以上。这是首次报道直接用光
化学方法控制抗生素耐药细菌的生长,并展示了光开关抗生素在辐照和非辐照状态下的最高活性差异。此外,还发现这两种异构体对人体细胞无害。研究人员通过分子建模找出了辐照异构体与拓扑异构酶 IV 酶高亲和力结合的根本原因。