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Lookup NU author(s): Professor Waldemar Vollmer
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Author(s). mLife published by John Wiley & Sons Australia, Ltd on behalf of Institute of Microbiology, Chinese Academy of Sciences.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 Klebsiella pneumoniae (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.
Author(s): Mu Y, Song Y, Tian X, Ding Z, Yao S, Li Y, Wang C, Wei D, Vollmer W, Zhang G, Feng J
Publication type: Article
Publication status: Published
Journal: mLife
Year: 2025
Volume: 4
Issue: 2
Pages: 143-154
Print publication date: 01/04/2025
Online publication date: 18/03/2025
Acceptance date: 21/12/2024
Date deposited: 09/04/2025
ISSN (print): 2097-1699
ISSN (electronic): 2770-100X
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1002/mlf2.70003
DOI: 10.1002/mlf2.70003
Data Access Statement: Genomic sequence data for the phage-resistant mutants of the K. pneumonia Kp067 strain used in this study have been deposited into the National Center for Biotechnology Information (NCBI; https://www.ncbi.nlm.nih.gov/) under the BioProject accession no. PRJNA1100799. The genomic data for the three phages used in this study were deposited into the GenBank with accession no. OR532835 (RCIP0041), OR532796 (RCIP0002), and OR532864 (RCIP0070).
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