Phage therapy is becoming a widely recognized alternative for fighting pathogenic bacteria due to increasing antibiotic resistance problems. However, one of the common concerns related to the use of phages is the evolution of bacterial resistance against the phages, putatively disabling the treatment. Experimental adaptation of the phage (phage training) to infect a resistant host has been used to combat this problem. Yet, there is very little information on the trade-offs of phage infectivity and host range. Here we co-cultured a myophage FCV-1 with its host, the fish pathogen Flavobacterium columnare, in lake water and monitored the interaction for a one-month period. Phage resistance was detected within one day of co-culture in the majority of the bacterial isolates (16 out of the 18 co-evolved clones). The primary phage resistance mechanism suggests defense via surface modifications, as the phage numbers rose in the first two days of the experiment and remained stable thereafter. However, one bacterial isolate had acquired a spacer in its CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat)-Cas locus, indicating that also CRISPR-Cas defense was employed in the phage-host interactions. After a week of co-culture, a phage isolate was obtained that was able to infect 18 out of the 32 otherwise resistant clones isolated during the experiment. Phage genome sequencing revealed several mutations in two open reading frames (ORFs) likely to be involved in the regained infectivity of the evolved phage. Their location in the genome suggests that they encode tail genes. Characterization of this evolved phage, however, showed a direct cost for the ability to infect several otherwise resistant clones—adsorption was significantly lower than in the ancestral phage. This work describes a method for adapting the phage to overcome phage resistance in a fish pathogenic system.

中文翻译：

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使噬菌体适应噬菌体抗性。

由于越来越多的抗生素耐药性问题，噬菌体疗法已成为对抗病原细菌的广泛认可的替代方法。然而，与噬菌体的使用有关的普遍关注之一是细菌对噬菌体的抗性的演变，从而推定了该治疗的无效。噬菌体的实验适应性（噬菌体训练）以感染抗性宿主已用于解决该问题。但是，关于噬菌体感染性和寄主范围的权衡取舍的信息很少。在这里，我们共培养一个myophage FCV-1与其宿主，鱼类病原黄杆菌columnare在湖水中，并监控了一个月的互动。大多数细菌分离株（18个共同进化的克隆中有16个）在共培养的一天之内就检测到了噬菌体抗性。主要的噬菌体抗性机制通过表面修饰提示防御，因为噬菌体数在实验的前两天上升，此后保持稳定。然而，一种细菌分离物已在其CRISPR（聚簇有规律间隔的短回文重复序列）-Cas基因座中获得了一个间隔区，表明在噬菌体-宿主相互作用中也采用了CRISPR-Cas防御。共培养一周后，获得了噬菌体分离物，该噬菌体分离物能够感染实验过程中分离出的32个原本具有抗性的克隆中的18个。噬菌体基因组测序揭示了两个开放阅读框（ORF）中的几个突变，这些突变可能与进化的噬菌体的恢复感染力有关。它们在基因组中的位置表明它们编码尾巴基因。然而，这种进化的噬菌体的表征显示了感染几个原本具有抗性的克隆的能力的直接成本-吸附明显低于祖传噬菌体。这项工作描述了一种使噬菌体适应鱼类致病系统中的噬菌体抗性的方法。