高阶表观驱动进化的不可预测性,导致新型抗生素耐药性
Ilona Kamila Gaszek1,2,3, Muhammed Sadik Yildiz1,2,3, Devin Meng2,3
1Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
bioRxiv : the preprint server for biology
|July 17, 2025
概括
抗生素耐药性根据药物而不同地发展. 适应aztreonam等新药创造了复杂的进化路径,与适应安培素等旧药不同,提供了打击耐药性的新策略.
科学领域:
- 进化生物学是进化的生物学.
- 微生物学 微生物学
- 生物化学 生化学
背景情况:
- 扩展光谱β-乳酸酶 (ESBLs) 是全球主要的健康威胁,降低了广泛使用的β-乳酸酶抗生素的有效性.
- 了解抗生素耐药性的进化途径对于开发新药和新策略至关重要.
研究的目的:
- 通过创建一个全面的突变库来研究TEM-1β-乳糖酶耐药性的进化动态.
- 在来自原生抗生素 (安皮西林) 和新型抗生素 (阿兹特里诺姆) 的选择压力下分析健身景观.
- 为了确定表皮性相互作用和塑造抗生素耐药性的进化约束.
主要方法:
- 建立了一个55296个TEM-1β-乳糖酶变体库,其中有18个突变.
- 在安培和阿兹特雷诺南选择下进行了超过800万次健身测量.
- 利用图形理论,表观学和机器学习分析,包括直接合分析.
主要成果:
- 安皮西林的选择导致了较弱的表现和更平滑的健身景观.
- 阿兹特里奥纳姆的选择引发了广泛的高阶表观和崎的健身景观.
- 确定了对于阿兹特雷诺曼耐药性和保存的进化模式至关重要的上下文依赖的表皮相互作用.
结论:
- 高阶表达性显著影响酶适应新基质,创造了不可预测的进化轨迹.
- 这项研究为预测进化药理学提供了一个框架,以评估新的抗生素和新出现的耐药性.
- 基于图形理论的进化约束可以用来战略性地抑制抗生素耐药性的进化.
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