Han Pengjun, Lin Wei, Fan Huahao, Tong Yigang
College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China.
Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, China.
J Virol. 2024 Feb 20;98(2):e0124923. doi: 10.1128/jvi.01249-23. Epub 2024 Jan 8.
Phage therapy has become a viable antimicrobial treatment as an alternative to antibiotic treatment, with an increase in antibiotic resistance. Phage resistance is a major limitation in the therapeutic application of phages, and the lack of understanding of the dynamic changes between bacteria and phages constrains our response strategies to phage resistance. In this study, we investigated the changing trends of mutual resistance between () and its lytic phage, BUCT603. Our results revealed that resisted phage infection through mutations in the cell membrane proteins, while the evolved phage re-infected the resistant strain primarily through mutations in structure-related proteins. Compared with the wild-type strain (SMA118), the evolved phage-resistant strain (R118-2) showed reduced virulence, weakened biofilm formation ability, and reduced resistance to aminoglycosides. In addition, the evolved phage BUCT603B1 in combination with kanamycin could inhibit the development of phage-resistant and significantly improve the survival rate of -infected mice. Altogether, these results suggest that characterization of bacteria-phage co-evolutionary relationships is a useful research tool to optimize phages for the treatment of drug-resistant bacterial infections.IMPORTANCEPhage therapy is a promising approach to treat infections caused by drug-resistant . However, the rapid development of phage resistance has hindered the therapeutic application of phages. evolutionary studies of bacteria-phage co-cultures can elucidate the mechanism of resistance development between phage and its host. In this study, we investigated the resistance trends between and its phage and found that inhibition of phage adsorption is the primary strategy by which bacteria resist phage infection , while phages can re-infect bacterial cells by identifying other adsorption receptors. Although the final bacterial mutants were no longer infected by phages, they incurred a fitness cost that resulted in a significant reduction in virulence. In addition, the combination treatment with phage and aminoglycoside antibiotics could prevent the development of phage resistance in . These findings contribute to increasing the understanding of the co-evolutionary relationships between phages and .
随着抗生素耐药性的增加，噬菌体疗法已成为一种可行的抗菌治疗方法，可替代抗生素治疗。噬菌体抗性是噬菌体治疗应用中的一个主要限制，而对细菌与噬菌体之间动态变化的缺乏了解限制了我们应对噬菌体抗性的策略。在本研究中，我们调查了（）与其裂解性噬菌体BUCT603之间相互抗性的变化趋势。我们的结果表明，（）通过细胞膜蛋白的突变抵抗噬菌体感染，而进化后的噬菌体主要通过结构相关蛋白的突变重新感染抗性菌株。与野生型菌株（SMA118）相比，进化后的噬菌体抗性菌株（R118-2）的毒力降低，生物膜形成能力减弱，对氨基糖苷类药物的抗性降低。此外，进化后的噬菌体BUCT603B1与卡那霉素联合使用可抑制噬菌体抗性（）的发展，并显著提高（）感染小鼠的存活率。总之，这些结果表明，表征细菌 - 噬菌体的共同进化关系是优化噬菌体用于治疗耐药细菌感染的有用研究工具。重要性噬菌体疗法是治疗由耐药（）引起的感染的一种有前途的方法。然而，噬菌体抗性的快速发展阻碍了噬菌体的治疗应用。对细菌 - 噬菌体共培养的进化研究可以阐明噬菌体与其宿主之间抗性发展的机制。在本研究中，我们调查了（）与其噬菌体之间的抗性趋势，发现抑制噬菌体吸附是细菌抵抗噬菌体感染的主要策略，而噬菌体可以通过识别其他吸附受体重新感染细菌细胞。尽管最终的细菌突变体不再被噬菌体感染，但它们付出了适应性代价，导致毒力显著降低。此外，噬菌体与氨基糖苷类抗生素的联合治疗可以预防（）中噬菌体抗性的发展。这些发现有助于增进对噬菌体与（）之间共同进化关系的理解。
