Zoological Institute, Christian-Albrechts Universität zu Kiel, Kiel, Germany.
RD3 Marine Ecology, RU Marine Symbioses, GEOMAR Helmholtz Centre for Ocean Research, Kiel, Germany.
mSphere. 2024 Jul 30;9(7):e0070723. doi: 10.1128/msphere.00707-23. Epub 2024 Jun 27.
Phage therapy is increasing in relevance as an alternative treatment to combat antibiotic resistant bacteria. Phage cocktails are the state-of-the-art method of administering phages in clinical settings, preferred over monophage treatment because of their ability to eliminate multiple bacterial strains and reduce resistance formation. In our study, we compare monophage applications and phage cocktails to our chosen method of phage sequential treatments. To do so, we isolated four novel bacteriophages capable of infecting T3, a close relative of , and characterized them using sequencing and transmission electron microscopy. While investigating monophage treatments, we observed that different phage concentrations had a strong impact on the timing and amount of resistance formation. When using phage cocktails, we observed that were capable of forming resistance in the same timespan it took them to become resistant to single phages. We isolated mutants resistant to each single phage as well as mutants exposed to phage cocktails, resulting in bacteria resistant to all four phages at once. Sequencing these mutants showed that different treatments yielded unique single nucleotide polymorphism mutation patterns. In order to combat resistance formation, we added phages one by one in intervals of 24 h, thus managing to delay resistance development and keeping bacterial growth significantly lower compared to phage cocktails.IMPORTANCEWHO declared antimicrobial resistance a top threat to global health; while antibiotics have stood at the forefront in the fight against bacterial infection, the increasing number of multidrug-resistant bacteria highlights a need to branch out in order to address the threat of antimicrobial resistance. Bacteriophages, viruses solely infecting bacteria, could present a solution due to their abundance, versatility, and adaptability. For this study, we isolated new phages infecting a fast-mutating strain capable of forming resistance within 30 h. By using a sequential treatment approach of adding one phage after another, we were able to curb bacterial growth significantly more compared to state-of-the-art phage cocktails.
噬菌体疗法作为一种对抗抗生素耐药细菌的替代治疗方法的相关性日益增加。噬菌体鸡尾酒是在临床环境中管理噬菌体的最先进方法，优于单噬菌体治疗，因为它们能够消除多种细菌菌株并减少耐药性的形成。在我们的研究中，我们将单噬菌体应用和噬菌体鸡尾酒与我们选择的噬菌体顺序治疗方法进行了比较。为此，我们分离了四种能够感染 T3 的新型噬菌体，T3 是 的近亲，并使用测序和透射电子显微镜对其进行了表征。在研究单噬菌体治疗时，我们观察到不同的噬菌体浓度对耐药形成的时间和数量有很大影响。当使用噬菌体鸡尾酒时，我们观察到 在与单噬菌体产生耐药性相同的时间内就能够产生耐药性。我们分离出对每种单噬菌体都具有抗性的突变体以及暴露于噬菌体鸡尾酒的突变体，导致细菌同时对所有四种噬菌体都具有抗性。对这些突变体进行测序表明，不同的处理方法产生了独特的单核苷酸多态性突变模式。为了对抗耐药性的形成，我们每隔 24 小时添加一种噬菌体，从而成功地延迟了耐药性的发展，并使细菌生长明显低于噬菌体鸡尾酒。
重要性
世界卫生组织将抗微生物药物耐药性列为对全球健康的头号威胁；虽然抗生素在对抗细菌感染方面一直处于前沿，但越来越多的多药耐药细菌突出表明，需要开拓新途径来应对抗微生物药物耐药性的威胁。噬菌体，专门感染细菌的病毒，由于其丰富性、多功能性和适应性，可能是一种解决方案。在这项研究中，我们分离了新的噬菌体，感染了一种快速突变的 菌株，这种菌株能够在 30 小时内形成耐药性。通过采用一种逐个添加噬菌体的顺序治疗方法，与最先进的噬菌体鸡尾酒相比，我们能够显著抑制细菌的生长。
