Na+-V-ATPase抑制剂抑制了VRE的生长,并揭示了Na+通路结构
Kano Suzuki1,2,3, Yoshiyuki Goto3,4,5,6,7, Akihiro Otomo8,9
1Department of Chemistry, Graduate School of Science, Chiba University, Chiba, Japan.
Nature structural & molecular biology
|November 21, 2024
概括
一种新的化合物V-161通过向它的V-ATPase.有效地抑制了抗万科胺素的Enterococcus faecium (VRE) 的生长和殖民. 这一发现为对抗VRE感染提供了一个有希望的策略.
科学领域:
- 微生物学 微生物学
- 生物化学 生物化学
- 结构生物学 结构生物学
背景情况:
- 抗万科米辛的菌 (Enterococcus faecium,VRE) 是导致医院感染的重要原因之一.
- 现有的抗生素对VRE的疗效越来越低,需要新的治疗策略.
- Enterococcus物种中的Na+运输V-ATPase在细胞功能中起着至关重要的作用,特别是在性条件下.
研究的目的:
- 为了确定VRE生长的新型抑制剂.
- 研究已识别的抑制剂的作用机制.
- 阐明V-ATPase抑制的结构基础.
主要方法:
- 化合物库 (70,600种化合物) 的高通量选,以识别V-ATPase抑制剂.
- 在体外测试以评估V-ATPase活性抑制和VRE生长.
- 在体内研究以评估VRE殖民抑制在小鼠模型.
- 高分辨率结构分析V-ATPase VO域与抑制剂复合.
主要成果:
- 化合物V-161被确定为Enterococcus hirae V-ATPase活性的一个强有力的抑制剂.
- 在性条件下,V-161显著抑制了VRE生长.
- V-161显著抑制了小鼠小肠中的VRE殖民.
- 高分辨率结构揭示了V-161在c环和a子单元的接口上结合,阻止Na+运输和旋转.
结论:
- V-161是一种有前途的化合物,用于开发新的抗VRE疗法.
- 准运输Na+的V-ATPase是对抗VRE感染的可行策略.
- 对V-161结合的结构洞察力为针对VRE的合理药物设计提供了基础.
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