Pleiotropy complicates a trade-off between phage resistance and antibiotic resistance
Pleiotropy complicates a trade-off between phage resistance and antibiotic resistance
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DOI：
10.1073/pnas.1919888117
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发表时间：
2020-05-26
影响因子：
11.1
通讯作者：
Turner, Paul E.
中科院分区：
文献类型：
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作者：
Burmeister, Alita R.;Fortier, Abigail;Turner, Paul E.
细菌经常遇到抗生素和溶解噬菌体的选择。然而，抗生素和噬菌体之间的进化相互作用仍然不清楚，特别是，噬菌体是否以及何时可以推动进化权衡抗生素耐药性。在这里，我们描述了大肠杆菌噬菌体U136B，表明它依赖于参与不同抗生素耐药机制的两个宿主因子：1)外排泵蛋白TolC和2)结构屏障分子脂多糖（LPS）。由于TolC和LPS有助于抗生素耐药，噬菌体U136B应该选择它们的丢失或修饰，从而在噬菌体耐药和抗生素耐药机制之间进行权衡。为了验证这一假设，我们使用波动实验和实验进化来获得抗噬菌体突变体。利用这些突变体，我们将特定突变的可及性（在波动实验中揭示）与它们在生态竞争和共同进化中的实际成功（在进化实验中揭示）进行了比较。在波动实验中，tolC和lps相关突变都很容易出现，在进化实验中，tolC突变变得更常见。为了支持权衡假说，在许多情况下，通过tolC突变产生的噬菌体耐药性与抗生素耐药性的相应降低有关。然而，与假设相反，一些噬菌体耐药突变多效性地赋予抗生素耐药性增加。我们讨论了这种令人惊讶的多效性结果的分子机制，应用噬菌体生物学的考虑，以及生态学在噬菌体耐药性进化中的重要性。我们设想噬菌体可能有助于逆转抗生素耐药性，但这种应用将需要考虑意想不到的多效性和进化背景。
Bacteria frequently encounter selection by both antibiotics and lytic bacteriophages. However, the evolutionary interactions between antibiotics and phages remain unclear, in particular, whether and when phages can drive evolutionary trade-offs with antibiotic resistance. Here, we describe Escherichia coli phage U136B, showing it relies on two host factors involved in different antibiotic resistance mechanisms: 1) the efflux pump protein TolC and 2) the structural barrier molecule lipopolysaccharide (LPS). Since TolC and LPS contribute to antibiotic resistance, phage U136B should select for their loss or modification, thereby driving a trade-off between phage resistance and either of the antibiotic resistance mechanisms. To test this hypothesis, we used fluctuation experiments and experimental evolution to obtain phage-resistant mutants. Using these mutants, we compared the accessibility of specific mutations (revealed in the fluctuation experiments) to their actual success during ecological competition and coevolution (revealed in the evolution experiments). Both tolC and LPS-related mutants arise readily during fluctuation assays, with tolC mutations becoming more common during the evolution experiments. In support of the trade-off hypothesis, phage resistance via tolC mutations occurs with a corresponding reduction in antibiotic resistance in many cases. However, contrary to the hypothesis, some phage resistance mutations pleiotropically confer increased antibiotic resistance. We discuss the molecular mechanisms underlying this surprising pleiotropic result, consideration for applied phage biology, and the importance of ecology in evolution of phage resistance. We envision that phages may be useful for the reversal of antibiotic resistance, but such applications will need to account for unexpected pleiotropy and evolutionary context.