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全基因组基因表达调整揭示了M.结核病的各种脆弱性

Barbara Bosch¹, Michael A DeJesus¹, Nicholas C Poulton¹

¹Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, NY 10065, USA.

|July 23, 2021

概括

这项研究引入了基因脆弱性, 它通过量化部分抑制的适应性成本重新定义了必不可少的基因,有助于发现新的抗菌点.

科学领域:

细菌学和微生物遗传学
功能基因组学和药物发现

背景情况:

传统的方法将基本基因定义为全部或没有,无法识别部分抑制导致显著的健康成本的目标.
现有的抗菌药物往往无法完全抑制标,从而限制了疗效,需要新的标识策略.

研究的目的:

开发和应用一种功能基因组学方法,以系统地评估Mycobacterium tuberculosis (Mtb) 的基因脆弱性.
根据基因脆弱性确定新的高价值抗菌药物标.
将不同Mtb菌株的基因脆弱性进行比较,并将其与抗菌敏感性相关联.

主要方法:

开发了一个基于CRISPR干扰 (CRISPRi) 的系统来定位Mtb的基因表达.
针对不同程度的基因抑制量化细菌健康结果.
进行基因脆弱性对照和高病毒性Mtb分离物的比较分析.

主要成果:

在各种细胞过程中确定了许多高度脆弱的基本基因,包括药物发现的新目标.
发现了不可攻击的基因, 可能解释了过去的药物发现失败.
表明Mtb菌株的基因脆弱性并未完全保留,并且可以预测差异化的抗菌敏感性.

结论:

基因脆弱性为重新定义重要细菌过程和识别优异药物点提供了定量衡量标准.
这种方法通过专注于部分抑制严重影响细菌健康的基因来增强新型抗菌剂的发现.
Mtb菌株间的基因差异脆弱性提供了有关菌株特异性药物反应和潜在耐药机制的见解.

关键词:

贝叶斯定理克里斯普尔-卡斯系统药物开发基本的基因质谱学类细菌类细菌结核菌脆弱性

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