大规模的化学遗传学产生了新的M.结核抑制剂类
Eachan O Johnson1,2,3, Emily LaVerriere1,4, Emma Office1
1Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nature
|June 21, 2019
概括
对结核病 (TB) 的新药发现至关重要. 通过对缺乏基本基因的细菌菌株进行测试, 发现了十倍以上的潜在抗生素化合物,
科学领域:
- 微生物学
- 药物发现
- 遗传学
背景情况:
- 越来越多的抗生素耐药性需要新的治疗策略,特别是在 Mycobacterium 结核病 (Mtb) 中.
- 传统的查方法已被证明不足以识别新的Mtb药物.
研究的目的:
- 开发和验证一种新的查方法PROSPECT,用于识别针对Mtb的新型抗生素化合物.
- 通过结合遗传信息来克服传统查的局限性.
主要方法:
- 针对 474 个基本基因的工程 Mtb 菌株.
- 检查了这些基因组的组合库.
- 分析了超过850万种化学基因相互作用以确定活性化合物及其标.
主要成果:
- 与查野生型Mtb相比,Prospect发现了十倍以上的成功.
- 化学基因相互作用提供了对化合物标的直接见解.
- 发现了40多种针对DNA旋转酶,细胞壁,酸盐生物合成,RNA聚合酶和EfpA的化合物.
- 优化的EfpA抑制剂对野生型Mtb表现出强烈的活性.
结论:
- 在发现针对Mtb的新型抗生素抑制剂方面,PROSPECT策略是有效的.
- 这种方法可以识别以前无法获得常规药物发现的目标抑制剂.
- 对于像Mtb这样的高优先病原体,PROSPECT可以加快药物候选物的识别.
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