Bypass of genetic constraints during mutator evolution to antibiotic resistance
Bypass of genetic constraints during mutator evolution to antibiotic resistance
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DOI：
10.1098/rspb.2014.2698
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发表时间：
2015-04-07
影响因子：
4.7
通讯作者：
Blazquez, Jesus
中科院分区：
文献类型：
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作者：
Couce, Alejandro;Rodriguez-Rojas, Alexandro;Blazquez, Jesus
在现实的适应环境中，遗传约束可以阻止许多通往最佳基因类型的突变途径，但这可以在多大程度上限制进化仍有待确定。有趣的是，突变细菌只提高特定类型的突变，因此可能对遗传限制非常敏感。测试这种可能性不仅与临床相关，而且还可以了解遗传限制在适应中的一般影响。在这里，我们进化了两个突变子和一个野生型大肠杆菌的576个种群，使抗生素头孢噻肟的浓度翻了一番。所有菌株都携带TEM-1，这是一种β-内酰胺酶，以其低突变途径而闻名。关键的是，其中一个突变子不会提升任何已知的提高头孢羟氨酶活性的相关第一步突变。尽管如此，这两个突变体都显示出相似的能力，可以进化出1000多倍的抗药性。最初的适应通过一般的多药耐药机制并行进行。相反，高水平的耐药性是通过不同的途径实现的；先天的劣质突变体利用抗生素的靶标PBP3中的替代突变途径。这些结果对临床感染中突变体的管理有一定的影响，更广泛地说，说明了现实生物中自然选择的限制因多个有助于适应的基因座的存在而得到缓解。
Genetic constraints can block many mutational pathways to optimal genotypes in real fitness landscapes, yet the extent to which this can limit evolution remains to be determined. Interestingly, mutator bacteria elevate only specific types of mutations, and therefore could be very sensitive to genetic constraints. Testing this possibility is not only clinically relevant, but can also inform about the general impact of genetic constraints in adaptation. Here, we evolved 576 populations of two mutator and one wild-type Escherichia coli to doubling concentrations of the antibiotic cefotaxime. All strains carried TEM-1, a beta-lactamase enzyme well known by its low availability of mutational pathways. Crucially, one of the mutators does not elevate any of the relevant first-step mutations known to improve cefatoximase activity. Despite this, both mutators displayed a similar ability to evolve more than 1000-fold resistance. Initial adaptation proceeded in parallel through general multi-drug resistance mechanisms. High-level resistance, in contrast, was achieved through divergent paths; with the a priori inferior mutator exploiting alternative mutational pathways in PBP3, the target of the antibiotic. These results have implications for mutator management in clinical infections and, more generally, illustrate that limits to natural selection in real organisms are alleviated by the existence of multiple loci contributing to fitness.