Adaptation to the fitness costs of antibiotic resistance in Escherichia coli
Adaptation to the fitness costs of antibiotic resistance in Escherichia coli
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DOI：
10.1098/rspb.1997.0178
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发表时间：
1997-09-22
影响因子：
4.7
通讯作者：
Levin, BR
中科院分区：
文献类型：
--
作者：
Schrag, SJ;Perrot, V;Levin, BR
旨在通过限制抗菌药物的使用来缓解日益严重的耐药病原体问题的政策隐含地假设，在没有药物的情况下，耐药性会降低病原体的达尔文适应性。虽然已经证明对某些化疗药物具有抗性的细菌和病毒具有适应成本，但预计这些成本在随后的进化过程中会下降。最近在艾滋病毒和大肠杆菌等多种病原体中观察到了这一点。在这里，我们提出的证据表明，这些对抗性成本的遗传适应实际上可以阻止抗性谱系恢复敏感性。我们表明，补偿大肠杆菌中链霉素抗性（rpsL）突变的大量（每代 14% 和 18%）适应成本的第二位点突变创造了一个遗传背景，其中链霉素敏感的 rpsL(+) 等位基因相对于适应的抗性菌株每代有 4-30% 的选择性劣势。我们还提供了证据，表明类似的补偿性突变已在长期耐链霉素的大肠杆菌实验室菌株中得到修复，这可能是在没有抗生素的情况下，在超过 10 000 代的群体中持续存在 rpsL 链霉素耐药性的原因。我们讨论了这些和其他实验结果对公共卫生的影响，这些结果质疑更谨慎地使用抗菌化疗是否会导致耐药病原微生物发生率的下降。
Policies aimed at alleviating the growing problem of drug-resistant pathogens by restricting antimicrobial usage implicitly assume that resistance reduces the Darwinian fitness of pathogens in the absence of drugs. While fitness costs have been demonstrated for bacteria and viruses resistant to some chemotherapeutic agents, these costs are anticipated to decline during subsequent evolution. This has recently been observed in pathogens as diverse as HIV and Escherichia coli. Here we present evidence that these genetic adaptations to the costs of resistance can virtually preclude resistant lineages from reverting to sensitivity. We show that second site mutations which compensate for the substantial (14 and 18% per generation) fitness costs of streptomycin resistant (rpsL) mutations in E. coli create a genetic background in which streptomycin sensitive, rpsL(+) alleles have a 4-30% per generation selective disadvantage relative to adapted, resistant strains. We also present evidence that similar compensatory mutations have been fixed in long-term streptomycin-resistant laboratory strains of E. coli and may account for the persistence of rpsL streptomycin resistance in populations maintained for more than 10 000 generations in the absence of the antibiotic. We discuss the public health implications of these and other experimental results that question whether the more prudent use of antimicrobial chemotherapy will lead to declines in the incidence of drug-resistant pathogenic microbes.