近日,国际著名杂志《自然—遗传学》Nature Genetics在线刊登了国外研究人员的最新研究成果“Evolutionary paths to antibiotic resistance under dynamically sustained drug selection。”,大肠杆菌在抗生素治疗过程中获得了药物抗性。研究人员对抗药性获得过程的大肠杆菌菌株进行了全基因组测序,这些实验是在一种新开发的实验室微生物培养设备中进行的,可实时监测细菌种群内药物抗性的基因组演变。
Roy Kishony和同事研制出一种名为“morbidostat”的设备,可在延长时间内自动进化实验。通过监测细菌生长并调整药物浓度以提供一种恒定选择压力,morbidostat提供了一种更真实的抗性演变实验室模型。利用这种morbidostat,在所选择的几个单一药物之一中,研究人员检测了大肠杆菌药物抗性的演化过程。他们测出了最初对药物敏感的大肠杆菌的全基因组序列,以及在25天的药物使用过程中所分离出这种细菌的全基因组序列。他们鉴别出赋予变异的新药物抗性,同时洞察到抗性演化过程中的变异顺序和通道。(生物谷Bioon.com)
doi:10.1038/ng.1034
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Evolutionary paths to antibiotic resistance under dynamically sustained drug selection
Erdal Toprak, Adrian Veres, Jean-Baptiste Michel, Remy Chait, Daniel L Hartl & Roy Kishony
Antibiotic resistance can evolve through the sequential accumulation of multiple mutations1. To study such gradual evolution, we developed a selection device, the 'morbidostat', that continuously monitors bacterial growth and dynamically regulates drug concentrations, such that the evolving population is constantly challenged2, 3, 4, 5. We analyzed the evolution of resistance in Escherichia coli under selection with single drugs, including chloramphenicol, doxycycline and trimethoprim. Over a period of ~20 days, resistance levels increased dramatically, with parallel populations showing similar phenotypic trajectories. Whole-genome sequencing of the evolved strains identified mutations both specific to resistance to a particular drug and shared in resistance to multiple drugs. Chloramphenicol and doxycycline resistance evolved smoothly through diverse combinations of mutations in genes involved in translation, transcription and transport3. In contrast, trimethoprim resistance evolved in a stepwise manner1, 6, through mutations restricted to the gene encoding the enzyme dihydrofolate reductase (DHFR)7, 8. Sequencing of DHFR over the time course of the experiment showed that parallel populations evolved similar mutations and acquired them in a similar order9.