Antiviral Resistance and Phage Counter Adaptation to Antibiotic-Resistant Extraintestinal Pathogenic Escherichia coli.
Antiviral Resistance and Phage Counter Adaptation to Antibiotic-Resistant Extraintestinal Pathogenic Escherichia coli.
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耐药肠外致病性大肠杆菌的抗病毒耐药性和噬菌体对抗适应。
DOI：
10.1128/mbio.00211-21
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发表时间：
2021-04-27
期刊：
影响因子：
6.4
通讯作者：
Maresso AW
中科院分区：
文献类型：
--
作者：
Salazar KC;Ma L;Green SI;Zulk JJ;Trautner BW;Ramig RF;Clark JR;Terwilliger AL;Maresso AW
肠外致病性大肠埃希菌（ExPEC），往往是多药耐药（MDR），是泌尿道和全身感染的主要原因。新出现的MDR病原体的危机导致一些人提出噬菌体作为治疗剂。肠外致病性大肠埃希菌（ExPEC），往往是多药耐药（MDR），是泌尿道和全身感染的主要原因。新出现的MDR病原体的危机导致一些人提出噬菌体作为治疗剂。然而，细菌对噬菌体的耐药性是一个令人担忧的问题，可能会破坏噬菌体治疗。在这里，我们证明了E。大肠杆菌序列类型131，一种ExPEC的流行性流行菌株，迅速产生对充分研究的和治疗活性的噬菌体（HP 3）的抗性。抗性的全基因组测序揭示了参与脂多糖（LPS）生物合成、外膜转运蛋白ompA或两者的基因的截短，暗示它们是噬菌体受体。我们发现ExPEC对噬菌体的抗性与宿主微环境中的适应性丧失和全身感染小鼠模型中的衰减有关。此外，我们构建了一种新的噬菌体-细菌生物反应器，以产生一种进化的噬菌体分离株，该噬菌体分离株对所有LPS截短的ExPEC抗性株都具有恢复的感染性。这项研究表明，虽然大流行E。大肠杆菌对噬菌体的感染是常见的，它与毒力的减弱和对定向进化产生的新噬菌体变体的易感性有关。
Extraintestinal pathogenic Escherichia coli (ExPEC), often multidrug resistant (MDR), is a leading cause of urinary tract and systemic infections. The crisis of emergent MDR pathogens has led some to propose bacteriophages as a therapeutic. Extraintestinal pathogenic Escherichia coli (ExPEC), often multidrug resistant (MDR), is a leading cause of urinary tract and systemic infections. The crisis of emergent MDR pathogens has led some to propose bacteriophages as a therapeutic. However, bacterial resistance to phage is a concerning issue that threatens to undermine phage therapy. Here, we demonstrate that E. coli sequence type 131, a circulating pandemic strain of ExPEC, rapidly develops resistance to a well-studied and therapeutically active phage (ϕHP3). Whole-genome sequencing of the resisters revealed truncations in genes involved in lipopolysaccharide (LPS) biosynthesis, the outer membrane transporter ompA, or both, implicating them as phage receptors. We found ExPEC resistance to phage is associated with a loss of fitness in host microenvironments and attenuation in a murine model of systemic infection. Furthermore, we constructed a novel phage-bacterium bioreactor to generate an evolved phage isolate with restored infectivity to all LPS-truncated ExPEC resisters. This study suggests that although the resistance of pandemic E. coli to phage is frequent, it is associated with attenuation of virulence and susceptibility to new phage variants that arise by directed evolution.