具有双重细菌膜和DNA向的Oligopyridinium型抗菌剂作为耐药抗菌剂
Jiaqi Li1, He Cao2, Peiren Chen3
1Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, and Department of Chemistry, Hunan University, Changsha, 410082, China; College of Biology, Hunan University, Changsha, Hunan, 410082, China.
European journal of medicinal chemistry
|August 4, 2025
概括
新的抗微生物类药物向细菌膜和DNA,提供了对抗具有广泛活性和低毒性多抗药性感染的有希望的战略.
科学领域:
- 药用化学 医学化学
- 发现抗微生物药物 发现抗微生物药物
- 分子生物学分子生物学
背景情况:
- 耐多药性 (MDR) 细菌感染构成了严重的全球健康威胁,推动了对新型抗生素的需求.
- 抗微生物模仿剂 (AMPMs) 是有前途的,但在标选择性和毒性方面面临挑战.
- 酸化合物为开发选择性抗菌剂提供了潜在的支架.
研究的目的:
- 为了设计和合成新型的基基基基基胺基.
- 评估这些化合物的抗菌活性和生物安全性.
- 阐明化合物对MDR细菌的作用机制.
主要方法:
- 氨基化寡二衍生物的合成.
- 对细菌组的最小抑制度 (MIC) 的确定.
- 细胞测试以评估膜相互作用,脱极化和DNA结合.
- 反应性氧物种 (ROS) 生产和代谢活动测试.
- 在感染模型中的体外和体内疗效研究 (绵羊血液,哺乳动物细胞,Galleria mellonella,小鼠MRSA模型).
- 在各种模型生物体中进行毒性评估.
主要成果:
- 一种化合物1c显示出强大的广泛抗菌活性 (MIC ≤2μg/mL).
- 化合物1c选择性地向细菌膜 (酸糖醇,脂多糖) 和DNA,导致膜脱极化,穿孔,ROS积累和代谢抑制.
- 1c迅速 (在2小时内) 根除休眠和持久性细菌,并在复杂的生物基质中显示出有效性.
- 在G. mellonella,斑马鱼或小鼠中没有观察到的有毒性,在20毫克/公斤的剂量下,生物安全性非常好.
- 在体内研究显示显著减少细菌负载,在G. mellonella中生存率为55%,在小鼠MRSA感染模型中生存率为75%.
结论:
- 新型阿米达聚胺胺基表现出强大的双重向抗菌性质.
- 化合物1c证明了广泛的疗效,快速作用和有利的安全性.
- 这些化合物代表了对抗具有挑战性的多药耐药性细菌感染的有希望的新战略.
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