巨型蛋白向细菌核糖体和DNA回旋酶,可以逃避抵抗机制
Elena V Aleksandrova1, Cong-Xuan Ma2, Dorota Klepacki3,4
1Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, USA.
Nature chemical biology
|July 22, 2024
概括
针对细菌核糖体和DNA回转酶的新型宏类抗生素在克服抗生素耐药性方面表现有前途. 与单一向药物相比,这些双重作用化合物不太可能产生耐药性.
科学领域:
- 微生物学 微生物学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 增加抗生素对宏类药物的耐药性需要新的治疗策略.
- 麦克罗隆,麦克罗利德衍生品与金诺龙部分,表现出强烈的活性,但它们的作用机制尚不清楚.
研究的目的:
- 为了阐明麦克罗隆抗生素的作用模式.
- 为了研究巨-核糖体相互作用的结构基础.
- 为了评估宏隆对抗耐药细菌菌株的疗效.
主要方法:
- 进行X射线晶体学,以确定与核糖体结合的巨蛋白的结构.
- 在体外生化测试以评估核糖体和DNA拓酶的抑制.
- 细菌生长抑制试验用于评估抗生素活性和耐药性发展.
主要成果:
- 麦克罗隆结合于核糖体出口道中的化物结合部位,而类组形成了新的相互作用.
- 麦克罗隆在体外抑制了核糖体功能和DNA陀皮索马酶 (DNA陀皮索马酶) 的活性.
- 在体内,宏隆可以向核糖体或DNA回旋酶,或两者兼而有之,有效地对抗耐药细菌.
结论:
- 双重向的宏隆对具有现有耐药机制的细菌有效,包括ERM介导的耐药性.
- 这些化合物在选择耐药突变物方面表现出较低的倾向,与传统的宏化物或诺基诺相比.
- 巨型抗生素是一种有希望的抗生素类别,用于应对抗菌素耐药性的挑战.
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