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首页> 外文期刊>BMC Microbiology >Lysis-deficient phages as novel therapeutic agents for controlling bacterial infection
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Lysis-deficient phages as novel therapeutic agents for controlling bacterial infection

机译：裂解不足的噬菌体作为控制细菌感染的新型治疗剂

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Background Interest in phage therapy has grown over the past decade due to the rapid emergence of antibiotic resistance in bacterial pathogens. However, the use of bacteriophages for therapeutic purposes has raised concerns over the potential for immune response, rapid toxin release by the lytic action of phages, and difficulty in dose determination in clinical situations. A phage that kills the target cell but is incapable of host cell lysis would alleviate these concerns without compromising efficacy. Results We developed a recombinant lysis-deficient Staphylococcus aureus phage P954, in which the endolysin gene was rendered nonfunctional by insertional inactivation. P954, a temperate phage, was lysogenized in S. aureus strain RN4220. The native endolysin gene on the prophage was replaced with an endolysin gene disrupted by the chloramphenicol acetyl transferase (cat) gene through homologous recombination using a plasmid construct. Lysogens carrying the recombinant phage were detected by growth in presence of chloramphenicol. Induction of the recombinant prophage did not result in host cell lysis, and the phage progeny were released by cell lysis with glass beads. The recombinant phage retained the endolysin-deficient genotype and formed plaques only when endolysin was supplemented. The host range of the recombinant phage was the same as that of the parent phage. To test the in vivo efficacy of the recombinant endolysin-deficient phage, immunocompromised mice were challenged with pathogenic S. aureus at a dose that results in 80% mortality (LD80). Treatment with the endolysin-deficient phage rescued mice from the fatal S. aureus infection. Conclusions A recombinant endolysin-deficient staphylococcal phage has been developed that is lethal to methicillin-resistant S. aureus without causing bacterial cell lysis. The phage was able to multiply in lytic mode utilizing a heterologous endolysin expressed from a plasmid in the propagation host. The recombinant phage effectively rescued mice from fatal S. aureus infection. To our knowledge this is the first report of a lysis-deficient staphylococcal phage.
机译：背景技术由于细菌病原体中抗生素抗性的迅速出现，过去十年来对噬菌体治疗的兴趣不断增长。然而，将噬菌体用于治疗目的引起了人们对免疫应答的潜力，通过噬菌体的裂解作用快速释放毒素以及在临床情况下确定剂量的困难的关注。杀死靶细胞但不能宿主细胞裂解的噬菌体将在不影响功效的情况下减轻这些担忧。结果我们开发了一种重组裂解不足的金黄色葡萄球菌噬菌体P954，其中的溶血素基因因插入失活而失去功能。 P954，一种温和的噬菌体，在金黄色葡萄球菌RN4220菌株中被裂解。通过使用质粒构建体的同源重组，将原噬菌体上的天然内皮素基因替换为被氯霉素乙酰基转移酶（cat）基因破坏的内皮素基因。通过在氯霉素存在下生长来检测携带重组噬菌体的溶原菌。重组原噬菌体的诱导没有导致宿主细胞裂解，并且通过用玻璃珠裂解细胞释放了噬菌体后代。重组噬菌体保留了内溶素缺乏的基因型，并且仅在补充内溶素时才形成噬菌斑。重组噬菌体的宿主范围与亲本噬菌体的宿主范围相同。为了测试重组内溶素缺乏缺陷型噬菌体的体内功效，用致病性金黄色葡萄球菌攻击免疫受损的小鼠，其剂量可导致80％的死亡率（LD 80 ）。用内溶素缺乏的噬菌体治疗使小鼠免受致命的金黄色葡萄球菌感染。结论已开发出重组的缺乏溶血素的葡萄球菌噬菌体，该噬菌体对耐甲氧西林的金黄色葡萄球菌具有致死性，而不会引起细菌细胞裂解。噬菌体能够利用从繁殖宿主中的质粒表达的异源内溶素以裂解模式繁殖。重组噬菌体有效地拯救了小鼠免受致命的金黄色葡萄球菌感染。据我们所知，这是裂解缺陷型葡萄球菌噬菌体的首次报道。

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