针对耐药性感染的新型抗生素的合理设计
Thomas F Durand-Reville1, Alita A Miller1, John P O'Donnell1
1Entasis Therapeutics, Waltham, MA, USA.
Nature
|September 16, 2021
概括
研究人员开发了一种新型抗生素ETX0462, 这种新化合物克服了关键的抵抗机制, 提供了对危险感染的希望.
科学领域:
- 医学化学
- 微生物学
- 药物发现
背景情况:
- 全球抗生素耐药性日益增加, 需要针对格拉姆阴性细菌感染的新疗法.
- 现有疗法受到β-乳糖酶和外膜无性等抵抗机制的挑战.
研究的目的:
- 设计针对格拉姆阴性细菌中的青素结合蛋白的新型抗氧化素抑制剂.
- 克服多种抵抗机制,包括β-乳糖酶活性和外膜透.
主要方法:
- 对于diazabicyclooctane化合物的合理设计.
- 重新设计化合物以获得体内疗效和目标光谱.
- 优化毛细菌的透性以及生化功效.
主要成果:
- 开发了一种具有强烈体外和体外活性的新型抗生素ETX0462.
- ETX0462对 Pseudomonas aeruginosa,ESKAPE病原体,Stenotrophomonas maltophilia和生物威胁病原体显示出有效性.
- 在β-乳糖酶存在的情况下,该化合物保持活性,并克服外膜屏障.
结论:
- ETX0462代表了一种有前途的新化学型,用于治疗危及生命的格拉姆阴性细菌感染.
- 该化合物的良好的临床前安全性支持潜在的临床开发.
- 这标志着抗生素耐药性在过去25年中的重大进展.
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