Parallel Evolution of High-Level Aminoglycoside Resistance in Escherichia coli Under Low and High Mutation Supply Rates
Parallel Evolution of High-Level Aminoglycoside Resistance in Escherichia coli Under Low and High Mutation Supply Rates
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DOI：
10.3389/fmicb.2018.00427
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发表时间：
2018-03-19
影响因子：
5.2
通讯作者：
Blazquez, Jesus
中科院分区：
文献类型：
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作者：
Ibacache-Quiroga, Claudia;Oliveros, Juan C.;Blazquez, Jesus
抗生素耐药性是世界范围内公共卫生的一个主要问题，因此人们对描述易感细菌进化出耐药性的突变途径非常感兴趣。本研究以庆大霉素为模型，在低突变供给率和高突变供给率下，利用实验进化方法探索氨基糖苷类耐药的突变途径。我们的研究结果表明，正常和超变大肠杆菌菌株都能够对药物剂量产生比其祖先的最低抑制浓度高100 - 1000倍的耐药性。有趣的是，这种耐药性水平通常与对其他抗生素的敏感性变化有关，最突出的是对磷霉素的耐药性增加。全基因组测序显示，所有耐药衍生物在5个常见遗传元件（fhuA、fusA和atpIBEFHAGDC、cyoABCDE和potABCD操纵子）上出现不同的突变。尽管获得了大量的突变，但超可变菌株显然没有付出适应性成本。与最近的研究相反，我们发现突变供应率主要影响进化的速度（节奏），而不是模式（模式）：两种背景都以相同的顺序获得突变，尽管超突变菌株更快。这一观察结果与庆大霉素高水平耐药的适应性景观相一致，相对平稳，很少出现局部最大值；这可能是耐药性涉及多个基因座的抗生素的共同特征。
Antibiotic resistance is a major concern in public health worldwide, thus there is much interest in characterizing the mutational pathways through which susceptible bacteria evolve resistance. Here we use experimental evolution to explore the mutational pathways toward aminoglycoside resistance, using gentamicin as a model, under low and high mutation supply rates. Our results show that both normo and hypermutable strains of Escherichia coli are able to develop resistance to drug dosages > 1,000-fold higher than the minimal inhibitory concentration for their ancestors. Interestingly, such level of resistance was often associated with changes in susceptibility to other antibiotics, most prominently with increased resistance to fosfomycin. Whole-genome sequencing revealed that all resistant derivatives presented diverse mutations in five common genetic elements: fhuA, fusA and the atpIBEFHAGDC, cyoABCDE, and potABCD operons. Despite the large number of mutations acquired, hypermutable strains did not pay, apparently, fitness cost. In contrast to recent studies, we found that the mutation supply rate mainly affected the speed (tempo) but not the pattern (mode) of evolution: both backgrounds acquired the mutations in the same order, although the hypermutator strain did it faster. This observation is compatible with the adaptive landscape for high-level gentamicin resistance being relatively smooth, with few local maxima; which might be a common feature among antibiotics for which resistance involves multiple loci.