符合性限制塑造了多种药物排泄适应蛋白的抑制
Benjamin Russell Lewis1, Muhammad R Uddin2, Mohammad Moniruzzaman2
1Department of Chemistry, King's College London, Britannia House, 7 Trinity Street, London, SE1 1DB, UK.
Nature communications
|July 18, 2023
概括
研究人员确定了抑制剂如何稳定AcrA蛋白,这是细菌多药耐药性的关键组成部分. 这种稳定性阻断了基本的通信,通过恢复药物的有效性来打击抗生素耐药性的新策略.
科学领域:
- 微生物学 微生物学
- 结构生物学 结构生物学
- 生物化学 生物化学
背景情况:
- 细菌的多药耐药性 (MDR) 是一个重大的全球健康威胁.
- 溢出,就像大肠杆菌的AcrAB-TolC系统一样,是MDR的主要贡献者.
- 针对这些,特别是AcrA适应蛋白,对于开发新的抗菌战略至关重要.
研究的目的:
- 通过向AcrA蛋白来阐明AcrAB-TolC排泄的抑制机制.
- 了解AcrA的结构动态以及抑制剂如何与其相互作用.
- 为开发新型抗微生物疗法提供见解.
主要方法:
- /交换质谱法 (HDX-MS) 用于分析蛋白质动态.
- 细胞流量测试测量药物运输.
- 分子动力学 (MD) 模拟用于模拟抑制剂-蛋白相互作用.
主要成果:
- 一种抑制剂稳定了AcrA在所有四个域中,与流出基质不同.
- 该抑制剂在AcrA的脂和αβ桶域之间的裂中充当分子.
- 这种形作用破坏了从AcrB到TolC的构造信号传输.
结论:
- 与AcrA结合的抑制剂稳定了其结构,并损害了其在排水中的功能.
- 这种机制为克服细菌的多药耐药性提供了一种新的方法.
- 这些发现对于设计新药来对抗抗生素耐药细菌有价值.
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