Evolutionary paths to antibiotic resistance under dynamically sustained drug selection.
Evolutionary paths to antibiotic resistance under dynamically sustained drug selection.
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DOI：
10.1038/ng.1034
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发表时间：
2011-12-18
期刊：
影响因子：
30.8
通讯作者：
Kishony, Roy
中科院分区：
文献类型：
--
作者：
Toprak, Erdal;Veres, Adrian;Michel, Jean-Baptiste;Chait, Remy;Hartl, Daniel L.;Kishony, Roy
抗生素耐药性可以通过多种突变的连续积累而进化。为了研究这种渐进的进化，我们开发了一种选择装置，morbidostat，它可以持续监测细菌的生长并动态调节药物浓度，从而不断挑战进化的种群。我们分析了大肠杆菌种群对氯霉素、强力霉素和甲氧苄啶耐药的进化轨迹。在大约20天的时间内，抗性水平急剧上升，平行种群表现出相似的表型轨迹。全基因组测序揭示了药物特异性和药物一般遗传变化。氯霉素和强力霉素耐药性是通过参与翻译、转录和转运的基因突变的不同组合进化而来的。相比之下，甲氧苄氨嘧啶耐药性是通过限制靶酶二氢叶酸还原酶（DHFR）的突变逐步进化的。随着时间的推移，DHFR测序显示平行种群不仅进化出相似的突变，而且以相似的顺序获得突变。发现这种复发性基因型途径可能有助于耐药性的传播。
Antibiotic resistance can evolve through sequential accumulation of multiple mutations. To study such gradual evolution, we developed a selection device, the morbidostat, which continuously monitors bacterial growth and dynamically regulates drug concentrations such that the evolving population is constantly challenged. We analyzed evolutionary trajectories of Escherichia coli populations towards resistance to chloramphenicol, doxycycline, and trimethoprim. Over a period of ~20 days, resistance levels increased dramatically, with parallel populations showing similar phenotypic trajectories. Whole-genome sequencing revealed both drug-specific and drug-general genetic changes. Chloramphenicol and doxycycline resistance evolved through diverse combinations of mutations in genes involved in translation, transcription, and transport. In contrast, trimethoprim resistance evolved in a stepwise manner, through mutations restricted to the target enzyme dihydrofolate reductase (DHFR). Sequencing DHFR over time revealed that parallel populations not only evolved similar mutations, but also acquired them in similar order. Uncovering such recurrent genotypic pathways may help the spread of resistance.
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