保存的进化轨迹可以被扰乱,以防止在诺弗洛辛压力下抵抗进化,通过强迫Mycobacterium smegmatis在替代进化路径上
1Department of Chemical Engineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra 400076, India.
ACS infectious diseases
|July 3, 2024
概括
适应性实验室进化 (Adaptive Laboratory Evolution) 发现,阻断排泄可以延迟或阻止抗生素耐药性的发展,即使细菌暴露于诺夫洛克萨. 这一发现为细菌进化和耐药性机制提供了洞察力.
科学领域:
- 微生物学和分子生物学
- 进化生物学 进化生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 抗生素耐药性是一个关键的全球健康威胁,细菌耐药性超过了新药的开发速度.
- 适应性实验室进化 (ALE) 是研究抗性决定因素的关键方法.
- 药物剂量概况对细菌耐药性演变的影响尚不清楚.
研究的目的:
- 调查不同诺夫洛克萨剂量配置 (循环常数与逐步增加) 如何影响*Mycobacterium smegmatis*抗生素耐药性的进化途径.
- 为了确定在不同的药物暴露条件下选择的特定遗传突变和抗药机制.
- 探索排水,特别是LfrR调节器和LfrA在高电阻的发展中的作用.
主要方法:
- 适应性实验室进化 (ALE) 在*Mycobacterium smegmatis*上进行.
- 细菌被暴露在使用循环常数和逐步增加药物度的诺夫洛克萨辛中.
- 进行了基因分析,以确定进化的种群中的突变,包括与缺乏*lfrA*排泄的菌株进行比较.
主要成果:
- 在所有测试条件中,排水调节器LfrR的突变被一致选择,这表明基于排水的抵抗机制被保留了.
- 高水平的耐药性和随后的药物标突变仅在诺夫洛克萨辛度超过最低抑制度 (MIC) 的4倍时观察到.
- 在lfrR*,MSMEG_1959和MSMEG_5045中的突变组合赋予了高水平的耐药性,先于目标突变.
- 在缺乏 *lfrA* 流出的菌株中, *lfrR* 突变没有被选择,耐药性进化要么被阻止,要么被延迟,没有目标基因突变.
结论:
- 由LfrR调节的流量活动,在诺夫洛素耐药性发展的早期阶段起着至关重要的作用.
- 药物向突变需要显著更高的药物度才能出现.
- 抑制排泄表达可能会通过延迟或阻止药物向突变的固定来限制最大可实现的抗生素耐药性水平.
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