在监管网络枢纽的抗生素耐药性的药物治疗进化
Yin Zhai1, John P Pribis2,3, Sean W Dooling2,4
1Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Science advances
|June 23, 2023
概括
新药可以通过向突变发生来减缓细菌进化和抗生素耐药性. 甲化 (DEQ) 抑制了关键的应激反应,延长了抗生素的有效性,但没有促进耐药性.
科学领域:
- 微生物学 微生物学
- 分子生物学分子生物学
- 进化生物学 进化生物学
背景情况:
- 抗生素耐药性是一种由细菌突变驱动的全球健康危机.
- 迫切需要采取减缓细菌进化和延长抗生素疗效的策略.
- 针对突变发生的现有方法在很大程度上是无效的.
研究的目的:
- 使用基于网络的策略,识别抑制诺基诺抗生素诱导的突变发生的药物.
- 研究甲化 (DEQ) 影响细菌应激反应和突变发生的机制.
- 评估DEQ在感染期间减缓细菌进化的有效性.
主要方法:
- 基于网络的药物查,以确定突变发生中心的抑制剂.
- 研究严格的饥饿反应和一般应激反应途径的抑制.
- 评估DEQ对细菌进化和耐药性发展 in vitro 和 in vivo 的影响.
- 利用小鼠感染模型研究压力诱导的突变发生及其抑制.
主要成果:
- 鉴定了dequalinium化物 (DEQ),一种FDA/EMA批准的药物,作为诺基诺诱导的突变发生的抑制剂.
- DEQ阻止了严格的饥饿反应的激活,这是促进突变性DNA修复的关键步骤.
- DEQ有效地减缓了细菌进化的速度,而没有选择耐药突变物.
- 在使用DEQ的小鼠感染期间,已证明抑制了压力诱导的突变发生.
结论:
- 甲基化物 (DEQ) 提供了一种潜在的治疗策略,通过减缓细菌进化来打击抗生素耐药性.
- 针对压力反应提供了一种新的方法来开发增强抗生素寿命的药物.
- 基于网络的策略是发现进化减缓药物的可行方法.
- 在临床前模型中,DEQ证明了它的有效性,突出了其临床应用的潜力.
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