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大肠杆菌耐药机制 AcrAB-TolC 排泄与常用的抗生素的相互作用:一个分子动力学研究

Brooke L Smith¹, Sandun Fernando¹, Maria D King²

¹Aerosol Technology Laboratory, Biological and Agricultural Engineering Department, Texas A&M University, College Station, TX, 77843, USA.

Scientific reports

|February 1, 2024

概括

分子动力学模拟显示增加了压力,模仿了气溶化,通过改变排泄的灵活性和安培的结合,增强了阴性细菌的抗生素耐药性.

科学领域:

计算生物学和分子建模.
微生物学和抗生素耐药性的研究.
生物物理学和蛋白质动力学

背景情况:

格拉姆阴性细菌 (GNB) 由于抗生素耐药性增加,对全球健康构成重大威胁.
AcrAB-TolC排泄是大肠杆菌 (大肠杆菌) 抗生素耐药性的关键机制.
之前的研究表明,气溶应激增加了GNB的抗生素耐药性和排泄活动.

研究的目的:

在模拟的气溶应力下,可视化GNB排放的分子水平变化.
研究增加压力对抗生素与AcrB蛋白和AcrAB-TolC复合体结合的影响.
为了将分子动力学发现与抗生素耐药性的实验数据相关联.

主要方法:

在标准和增加压力下对AcrB和AcrAB-TolC蛋白质进行分子动力学 (MD) 模拟.
蛋白质灵活性 (RMSD,RMSF) 和 TolC 开放动态的分析.
使用分子力学与一般化出生和表面积溶解 (MM-GBSA) 计算联结蛋白结合的自由能量.

主要成果:

与标准压力模拟相比,增加的压力导致AcrB和AcrAB-TolC蛋白质的刚性更大.
MM-GBSA评分没有显示出显著的变化,但最强的评分是转移到替代口袋的配体.
在增加的压力下,安皮西林 (AMP) 结合显示了TolC排泄的最显著的开口,与实验性电阻数据保持一致.

结论:

模拟的气溶应力 (增加的压力) 影响了AcrAB-TolC排泄的结构动力学.
增加的压力增强了与安皮西林的相互作用,与观察到的实验性耐药性相关.
这些发现有助于理解抗生素耐药性的分子机制,并为缓解策略提供信息.

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