Data from: Lytic phages obscure the cost of antibiotic resistance in Escherichia coli

The long-term persistence of antibiotic-resistant bacteria depends on their fitness relative to other genotypes in the absence of drugs. Outside the laboratory, viruses that parasitize bacteria (phages) are ubiquitous, but costs of antibiotic resistance are typically studied in phage-free experimental conditions. We used a mathematical model and experiments with Escherichia coli to show that lytic phages strongly affect the incidence of antibiotic resistance in drug-free conditions. Under phage parasitism, the likelihood that antibiotic-resistant genetic backgrounds spread depends on their initial frequency, mutation rate and intrinsic growth rate relative to drug-susceptible genotypes, because these parameters determine relative rates of phage-resistance evolution on different genetic backgrounds. Moreover, the average cost of antibiotic resistance in terms of intrinsic growth in the antibiotic-free experimental environment was small relative to the benefits of an increased mutation rate in the presence of phages. This is consistent with our theoretical work indicating that, under phage selection, typical costs of antibiotic resistance can be outweighed by realistic increases in mutability if drug resistance and hypermutability are genetically linked, as is frequently observed in clinical isolates. This suggests the long-term distribution of antibiotic resistance depends on the relative rates at which different lineages adapt to other types of selection, which in the case of phage parasitism is probably extremely common, as well as costs of resistance inferred by classical in vitro methods.耐药细菌的长期存续，取决于其在无药物环境中相对于其他基因型的适合度。实验室之外，寄生细菌的病毒（噬菌体，phages）无处不在，但抗生素耐药性的适合度成本通常仅在无噬菌体的实验条件下被研究。我们结合数学模型与大肠杆菌（Escherichia coli）实验证实，裂解性噬菌体可在无药条件下显著影响抗生素耐药性的发生概率。在噬菌体寄生的环境中，耐药遗传背景的传播可能性，取决于其初始频率、突变率，以及相对于药物敏感基因型的固有生长速率——这是因为上述参数决定了不同遗传背景下噬菌体抗性进化的相对速率。此外，在无抗生素的实验环境中，以固有生长速率衡量的抗生素耐药性平均成本，相较于噬菌体存在时突变率提升所带来的收益而言微不足道。这与我们的理论研究结果相符：当抗生素耐药性与高突变性存在遗传连锁（该现象在临床分离菌株中十分常见）时，在噬菌体选择压力下，若突变率出现符合实际情况的提升，通常的抗生素耐药性成本可被抵消。由此可见，抗生素耐药性的长期分布，取决于不同谱系适应其他类型选择压力的相对速率——而噬菌体寄生这类场景大概率极为普遍——同时也取决于通过经典体外实验方法推断出的耐药性成本。