中文摘要：抗生素耐药细菌的进化有可能成为全球死亡的主要原因。这场危机重新燃起了人们对噬菌体治疗的兴趣。然而，细菌耐药性的产生也可能削弱这种疗法。为了对抗噬菌体耐药性的进化并改善治疗效果，建议在噬菌体用于治疗之前，通过在目标宿主上进化噬菌体来对抗耐药性(噬菌体训练)。研究发现，在体外，经过28天训练的噬菌体λtrn对细菌的抑制能力是未经训练的噬菌体的1000倍，抑制时间延长三到八倍。抑制时间的延长是由于多种因素导致的耐药性演变延迟所致。对λtrn产生耐药性的突变比常见突变低约100倍；目标细菌单个突变就可以进化出对未经训练的噬菌体的完全耐药性，但要进化出对λtrn的完全耐药性则需要多个突变。可见，对λtrn产生耐药性的突变比未经训练的噬菌体耐药性突变更难。此外，当耐药性进化时，λtrn能更好地进行抑制。一种改进λtrn的方法是通过与宿主基因组中失效的原噬菌体中的一个基因重组，从而使噬菌体的适应度加倍。这种来自宿主基因组的信息传递是一种高效的噬菌体培养模式。最后，研究还发现许多其他独立训练的λ噬菌体能够抑制细菌种群，支持训练在噬菌体治疗发展过程中可能发挥的重要作用。
外文摘要：The evolution of antibiotic-resistant bacteria threatens to become the leading cause of worldwide mortality. This crisis has renewed interest in the practice of phage therapy. Yet, bacteria's capacity to evolve resistance may debilitate this therapy as well. To combat the evolution of phage resistance and improve treatment outcomes, many suggest leveraging phages' ability to counter resistance by evolving phages on target hosts before using them in therapy (phage training). We found that in vitro, lambda trn, a phage trained for 28 d, suppressed bacteria similar to 1,000-fold for three to eight times longer than its untrained ancestor. Prolonged suppression was due to a delay in the evolution of resistance caused by several factors. Mutations that confer resistance to lambda trn are similar to 100x less common, and while the target bacterium can evolve complete resistance to the untrained phage in a single step, multiple mutations are required to evolve complete resistance to lambda trn. Mutations that confer resistance to lambda trn are more costly than mutations for untrained phage resistance. Furthermore, when resistance does evolve, lambda trn is better able to suppress these forms of resistance. One way that lambda trn improved was through recombination with a gene in a defunct prophage in the host genome, which doubled phage fitness. This transfer of information from the host genome is an unexpected but highly efficient mode of training phage. Lastly, we found that many other independently trained lambda phages were able to suppress bacterial populations, supporting the important role training could play during phage therapeutic development.
外文关键词：evolution；coevolution；resistance；phage therapy；phage training
作者：Borin, JM；Avrani, S；Barrick, JE；Petrie, KL；Meyer, JR
作者单位：Univ Calif San Diego；Univ Haifa；Univ Texas Austin；Tokyo Inst Technol
期刊名称：PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
期刊影响因子：9.412
出版年份：2021
出版刊次：23
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