细菌流量调节器防止细菌在巨和在模仿宿主环境的条件下生长
Samual C Allgood1, Chih-Chia Su2,3, Amy L Crooks1
1Molecular, Cellular Developmental Biology, University of Colorado Boulder, Boulder, CO, USA.
bioRxiv : the preprint server for biology
|October 3, 2023
概括
新的排泄调节器 (EPM) 针对格拉姆阴性细菌中的AcrB,抑制毒性. 这些化合物通过阻断有毒代谢物出口,特别是在巨细胞内,在破坏微生物感染方面表现有前途.
科学领域:
- 微生物学与传染病的研究
- 药物发现和开发 药物发现和开发
- 结构生物学 结构生物学
背景情况:
- 迫切需要针对微生物感染的新型抗菌药物战略.
- 细菌排泄,如AcrAB-TolC,是格兰氏阴性病原体的关键毒性因素.
- 针对这些为开发新的抗感染药物提供了一个有希望的途径.
研究的目的:
- 开发和描述针对 AcrAB-TolC 排水系统 AcrB 组件的新型排水调节器 (EPM).
- 评估这些EPM在破坏细菌毒性的有效性,特别是在模仿宿主环境的条件下.
- 研究EPM在抑制细菌生长和增强抗生素活性方面的作用机制.
主要方法:
- 使用SAFIRE (使用IntracellulaR Enterobacteriaceae的光显微镜检测抗感染药物的屏幕) 平台进行细胞内查.
- 采用药物化学设计和合成大约200种EPM化合物的类型.
- 使用冷电子显微镜 (cryo-EM) 确定了EPM类似于AcrB的结合模式,并评估了膜完整性.
主要成果:
- 确定了具有纳米分子功率的EPM类似物,它们与AcrB基质结合口袋结合.
- 证明EPM类似物不会破坏细菌膜潜力.
- 观察到EPM类似物具有细菌静止作用,在模仿巨细胞的条件下增强抗生素活性,其中AcrAB对于生长至关重要.
结论:
- 针对AcrB的EPM代表了对抗格兰氏阴性细菌感染的可行策略.
- 这些化合物特别干扰了通过AcrAB-TolC排泄出口有毒细菌代谢物.
- 通过抑制毒性和增强现有抗生素的疗效,EPM有可能破坏病变发生.
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