Leveraging collateral sensitivity to counteract the evolution of bacteriophage resistance in bacteria
Abstract 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 overco...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-04-01
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| Series: | mLife |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mlf2.70003 |
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| Summary: | Abstract 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. |
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| ISSN: | 2770-100X |