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APH抑制剂可以逆转Enterococcus casseliflavus中的氨基糖化物耐药性

Elise Kaplan^1,2, Laurent Chaloin¹, Jean-François Guichou³

¹Institut de Recherche en Infectiologie de Montpellier - IRIM, University of Montpellier, CNRS UMR 9004, 1919 route de Mende, 34293, Montpellier cedex 5, France.

|January 13, 2025

概括

研究人员发现了可以抵消细菌氨基糖化物耐药性的小分子. 一种化合物EK3非竞争性地抑制了关键酶,恢复了抗生素对抗耐药细菌的有效性,没有毒性.

科学领域:

微生物学微生物学
生物化学生物化学
药物发现药物发现药物发现

背景情况:

氨基甘油酸-转化酶 (APHs) 赋予细菌对氨基甘油酸抗生素的耐药性.
获得的APH介导的耐药性是一个重大的临床挑战,需要新的治疗策略.
杆菌 (Enterococcus casseliflavus) 是研究抗生素耐药性机制的一个相关模型.

研究的目的:

为了识别通过APH酶介导的抵消氨基糖化物耐药性的小分子.
探索全调节剂作为抗生素耐药性的策略的潜力.
验证用于药物发现的in silico选方法.

主要方法:

使用分子动力学模拟对12000个小分子进行in silico选,以识别APH酶中的全囊.
在体外测试高得分的化合物用于酶抑制.
结构-活性关系 (SAR) 研究以优化化合物.
在HeLa细胞上进行细菌敏感性测试和细胞毒性测试.

主要成果:

鉴定EK3,一个非竞争性抑制剂的APH2''-IVa,一种赋予抗 gentamicin 的酶.
通过SAR研究对EK3的优化产生了具有改善酶抑制的化合物.
最好的化合物恢复了多种氨基糖化物对耐药细菌的杀菌活性.
对于最有效的化合物在HeLa细胞中没有观察到毒性.

结论:

小分子可以有效地抵消APH介导的氨基糖化物耐药性.
对APH酶的全性抑制是开发新抗生素的可行策略.
在的药物发现方法可以加速新型抗菌剂的识别.
这项研究为开发针对抗氨基糖化物耐药细菌感染的新疗法提供了基础.

关键词:

这里是Allostery.抗生素耐药性抗生素耐药性抑制剂抑制剂抑制剂分子对接是分子对接.虚拟选是一个虚拟的选.

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