Evolutionary Trade-off Exploitation: Using Phage-Induced Virulence Attenuation to Resensitize Resistant Bacteria to Antibiotics

Yu et al. (2024) revealed that carbapenem-resistant K. pneumoniae mutants evolving phage resistance via galU mutations simultaneously lose virulence and gain antibiotic sensitivity. This suggests an exploitable evolutionary trade-off. I propose a sequential therapy where lytic phages are administered first to drive bacterial evolution toward sensitized states, followed by targeted antibiotics. Unlike conventional phage-antibiotic synergy (PAS), this approach intentionally selects for phage-resistant clones with pre-characterized collateral weaknesses. Using CRISPR-mediated gene editing (as in Yu et al.), we could map resistance mutations across pathogens and identify predictable "sensitization pathways." This challenges the assumption that phage resistance is purely detrimental—reframing it as a controllable vulnerability. The impact could be revolutionary for untreatable infections, turning bacterial evolution into a therapeutic tool.

References:

1. Phage-mediated virulence loss and antimicrobial susceptibility in carbapenem-resistant Klebsiella pneumoniae. Yanshuang Yu, Mengzhu Wang, Liuying Ju, Minchun Li, Mengshi Zhao, Hui Deng, Christopher Rensing, Qiu-e Yang, Shungui Zhou (2024). mBio.