Mu Yongqi, Song Yuqin, Tian Xueru, Ding Zixuan, Yao Shigang, Li Yi, Wang Chao, Wei Dawei, Vollmer Waldemar, Zhang Gang, Feng Jie
State Key Laboratory of Microbial Resources, Institute of Microbiology Chinese Academy of Sciences Beijing China.
College of Life Science University of Chinese Academy of Sciences Beijing China.
mLife. 2025 Mar 18;4(2):143-154. doi: 10.1002/mlf2.70003. eCollection 2025 Apr.
The escalating antibiotic resistance crisis poses a major global health threat. Bacteriophage therapy offers a promising alternative for combating multidrug-resistant infections. However, bacterial resistance to phages remains a significant hurdle. Innovative strategies are needed to overcome this challenge. In this study, we developed a phage cocktail based on our phage library, consisting of three phages that suppressed phage resistance of carbapenem-resistant hypervirulent (CR-hvKp). This cocktail capitalized on dual instances of collateral sensitivity, thereby constraining the evolution of phage resistance. The first-layered collateral sensitivity arose from overlapping coverage between capsular polysaccharide (CPS) and lipopolysaccharide (LPS), rendering the bacteria resistant to CPS-binding phages but more susceptible to LPS-binding phages. The second-layered collateral sensitivity resulted from an O serotype switch (from O1 to O2), causing resistance to O1 antigen-binding phages but increasing susceptibility to phages that target the O2 antigen. This dual-layered collateral sensitivity phage cocktail effectively mitigated infection caused by CR-hvKp in mice. Our research highlights the importance of the collateral sensitivity mechanism in counteracting the evolution of phage resistance and offers a sophisticated strategy for configuring phage cocktails to eliminate bacterial resistance.
不断升级的抗生素耐药性危机对全球健康构成了重大威胁。噬菌体疗法为对抗多重耐药感染提供了一种有前景的替代方案。然而，细菌对噬菌体的耐药性仍然是一个重大障碍。需要创新策略来克服这一挑战。在本研究中，我们基于噬菌体库开发了一种噬菌体鸡尾酒，它由三种噬菌体组成，可抑制耐碳青霉烯类高毒力（CR-hvKp）细菌的噬菌体耐药性。这种鸡尾酒利用了两种并行敏感性实例，从而限制了噬菌体耐药性的演变。第一层并行敏感性源于荚膜多糖（CPS）和脂多糖（LPS）之间的重叠覆盖，使细菌对结合CPS的噬菌体产生耐药性，但对结合LPS的噬菌体更敏感。第二层并行敏感性是由O血清型转换（从O1到O2）导致的，使细菌对结合O1抗原的噬菌体产生耐药性，但对靶向O2抗原的噬菌体敏感性增加。这种具有双层并行敏感性的噬菌体鸡尾酒有效减轻了小鼠体内由CR-hvKp引起的感染。我们的研究强调了并行敏感性机制在对抗噬菌体耐药性演变中的重要性，并提供了一种配置噬菌体鸡尾酒以消除细菌耐药性的精密策略。
