主体氧化压力为快速抗生素耐药性进化培养了菌根菌
Evan Pepper-Tunick1,2, Vivek Srinivas1, Fred D Mast3,4
1Institute for Systems Biology, Seattle, WA, USA.
Research square
|December 11, 2025
概括
在氧化应激基因中已经存在的突变加速了Mycobacterium tuberculosis (Mtb) 的耐药性. 主体免疫压力和氧化应激原始Mtb对异化物耐药性的快速演变,影响结核病控制.
科学领域:
- 微生物学 微生物学
- 遗传学 遗传学 是一个
- 药物耐药性 药物耐药性 药物耐药性
背景情况:
- 耐多药性结核菌 (Mtb) 对全球结核病控制构成重大威胁.
- 驱动Mtb药物耐药性快速演变的机制尚未完全理解.
- 现有的范式表明,抗性突变先于适应性适应.
研究的目的:
- 调查氧化应激反应基因中先前存在的突变如何影响Mtb.药物耐药性的演变.
- 挑战这样一种观念,即适应性补偿性适应总是跟随抵抗性突变.
- 探索宿主施加的氧化应激在加速Mtb耐药性的作用.
主要方法:
- 使用了Mycobacterium smegmatis mc2155 (Msm) 作为一个模型生物.
- 暴露于Msm的亚致死性异化 (INH) 度,以对低水平耐药性和耐受性 (LLRT) 突变进行选择.
- 使用贝叶斯分析分析临床Mtb分离物,并重新分析全基因组CRISPRi屏幕.
主要成果:
- 在ohrR中的功能丧失突变通过使其他有害突变成为可能,加速了高水平的INH耐药性.
- 亚致命的氧化应激,模仿宿主压力,在MSM中增加了三倍的INH耐药性演变的速度.
- 氧化应激反应基因的突变与临床Mtb分离物中的INH耐药性显著相关.
结论:
- 预先存在的氧化应激反应突变为Mtb快速获得高水平抗药性创造了宽容的背景.
- 宿主施加的氧化应激与其他因素协同作用,为抗性进化培养Mtb.
- 准氧化应激防御可能是减缓结核病抗生素耐药性出现的策略.
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