针对格兰阴性细菌的化学胺抗生素
Anatol Luther1, Matthias Urfer2, Michael Zahn3
1Polyphor AG, Allschwil, Switzerland.
Nature
|October 25, 2019
概括
新的合成抗生素可以对抗目前药物耐药的危险的阴性病原体. 这些新型化合物向细菌膜,对抗多抗药性感染和克服胆固醇抗性有前途.
科学领域:
- 医学化学
- 微生物学
- 药物发现
背景情况:
- 迫切需要新的抗生素,
- 最后的抗生素对这些多抗药性病原体的有效性正在减弱.
- 由于抗菌素耐药性,ESKAPE病原体对全球健康构成重大威胁.
研究的目的:
- 开发一种新型的合成抗生素,
- 研究这些新型仿制抗生素的作用机制.
- 评估针对MDR病原体的优化衍生物的疗效和药物特性.
主要方法:
- 设计和合成结合β-毛刺宏循环与多素/素天然产品架构的仿制抗生素.
- 对杀菌活性和作用机制的评估,包括与脂聚糖 (LPS) 和β-桶外膜蛋白Bamma的结合.
- 在体外和体内对优化衍生物的评估,以对抗多抗药性格兰氏阴性病原体,包括ESKAPE病原体.
- 对胆固醇耐药性和药物特性进行评估.
主要成果:
- 开发出具有强烈杀菌活性的合成仿制抗生素来对抗阳性病原体.
- 证明了一种双重的作用机制,包括LPS结合和抑制β- barrel折叠复合体中的Bama蛋白.
- 优化衍生品对包括ESKAPE病原体在内的一系列MDR阴性细菌具有很高的疗效.
- 在体外和体内克服了现有的胆固醇抗药机制,具有有利的药物特性.
结论:
- 这种新型合成抗生素在治疗由MDR阴性病原体引起的危及生命的感染方面具有显著的潜力.
- 双重的作用机制和克服耐药性的能力使这些化合物成为解决关键未满足医疗需求的有希望的候选者.
- 主要候选人正在进行临床前毒理学研究,为潜在的临床试验铺平道路.
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