塑体对硫胺抗生素耐药性的分子机制
Meenakshi Venkatesan1, Michael Fruci2,3, Lou Ann Verellen2,3
1Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, M5S 1A4, Canada.
Nature communications
|July 7, 2023
概括
硫胺耐药性涉及新型的Sul酶,它们对这些抗菌药物进行歧视. 硫酶中的特定Phe-Gly序列是这种抵抗机制的关键.
科学领域:
- 微生物学 微生物学
- 结构生物学 结构生物学
- 药物发现 药物发现 药物发现
背景情况:
- 硫胺 (硫) 是一种古老的抗菌药物,其向的是二二酸合成酶 (DHPS).
- 耐药性源于folP的突变或获取编码不敏感药物DHPS变异的sul基因.
- 基于硫的耐药性的机制仍然不太清楚.
研究的目的:
- 阐明基于硫的硫胺耐药性的分子机制.
- 确定Sul酶活性的结构和功能基础.
- 为了帮助开发新的硫胺抗生素.
主要方法:
- 硫1,硫2和硫3酶的X射线晶体学.
- 生物化学和生物物理分析.
- 突变分析和在E. coli中的跨补充.
- 硫胺耐药性的实验演变.
主要成果:
- 与DHPS相比,硫酶在pABA结合区域中表现出显著的结构重组.
- 硫酶中的Phe-Gly序列通过歧视硫胺,同时保留pABA结合,从而赋予耐药性.
- 实验进化产生了具有Phe-Gly插入的耐药DHPS变体,模仿Sul机制.
- 硫酶表现出增强的活性部位结构动力学.
结论:
- 菲-格莱基基因对介导的硫胺耐药性至关重要.
- 硫酶的结构和动态特性解释了它们的抵抗机制.
- 这些发现为设计新型硫胺物质提供了基础,这些新型硫胺物质对耐药性不太敏感.
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