Epigenetic modifications and metabolic gene mutations drive resistance evolution in response to stimulatory antibiotics.

IF 8.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Hui Lin, Donglin Wang, Qiaojuan Wang, Jie Mao, Lutong Yang, Yaohui Bai, Jiuhui Qu
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引用次数: 0

Abstract

The antibiotic resistance crisis, fueled by misuse and bacterial evolution, is a major global health threat. Traditional perspectives tie resistance to drug target mechanisms, viewing antibiotics as mere growth inhibitors. New insights revealed that low-dose antibiotics may also serve as signals, unexpectedly promoting bacterial growth. Yet, the development of resistance under these conditions remains unknown. Our study investigated resistance evolution under stimulatory antibiotics and uncovered new genetic mechanisms of resistance linked to metabolic remodeling. We documented a shift from a fast, reversible mechanism driven by methylation in central metabolic pathways to a slower, stable mechanism involving mutations in key metabolic genes. Both mechanisms contribute to a metabolic profile transition from glycolysis to rapid gluconeogenesis. In addition, our findings demonstrated that rising environmental temperatures associated with metabolic evolution accelerated this process, increasing the prevalence of metabolic gene mutations, albeit with a trade-off in interspecific fitness. These findings expand beyond the conventional understanding of resistance mechanisms, proposing a broader metabolic mechanism within the selective window of stimulatory sub-MIC antibiotics, particularly in the context of climate change.

表观遗传修饰和代谢基因突变驱动对刺激性抗生素的抗性进化。
抗生素滥用和细菌进化加剧了抗生素耐药性危机,这是一个重大的全球健康威胁。传统观点将耐药性与药物靶标机制联系起来,认为抗生素仅仅是生长抑制剂。新的见解表明,低剂量抗生素也可能作为信号,意想不到地促进细菌生长。然而,在这些条件下耐药性的发展仍然未知。我们研究了刺激抗生素下的耐药性进化,揭示了与代谢重塑相关的新的耐药性遗传机制。我们记录了一个由中心代谢途径中甲基化驱动的快速、可逆机制向涉及关键代谢基因突变的较慢、稳定机制的转变。这两种机制都有助于代谢谱从糖酵解到快速糖异生的转变。此外,我们的研究结果表明,与代谢进化相关的环境温度升高加速了这一过程,增加了代谢基因突变的发生率,尽管存在种间适应性的权衡。这些发现超越了对耐药机制的传统理解,在刺激性亚mic抗生素的选择性窗口内提出了更广泛的代谢机制,特别是在气候变化的背景下。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Systems Biology
Molecular Systems Biology 生物-生化与分子生物学
CiteScore
18.50
自引率
1.00%
发文量
62
审稿时长
6-12 weeks
期刊介绍: Systems biology is a field that aims to understand complex biological systems by studying their components and how they interact. It is an integrative discipline that seeks to explain the properties and behavior of these systems. Molecular Systems Biology is a scholarly journal that publishes top-notch research in the areas of systems biology, synthetic biology, and systems medicine. It is an open access journal, meaning that its content is freely available to readers, and it is peer-reviewed to ensure the quality of the published work.
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