Reconsidering phage-host evolutionary triad for antimicrobial resistance control

The escalating crisis of antimicrobial resistance (AMR) requires innovative interventions beyond conventional antibiotics. Bacteriophages, as natural bacterial predators, represent a promising alternative. However, their influence is governed by a dynamic evolutionary continuum that determines whether they eradicate or maintain AMR populations. This work introduces a tripartite evolutionary framework to elucidate phage-host interactions: (1) an antagonistic arms race state that drives the diversification of molecular defenses; (2) a selfish protection state in which phages enhance host fitness to secure their own persistence; and (3) ecological feedback mechanisms that regulate transitions between these states. The potential for manipulating these evolutionary states to transform AMR control strategies is examined. Recent metagenomic and mechanistic evidence indicates that the arms race state provides a genetic toolkit for targeting AMR pathogens, whereas the protective state, mediated by auxiliary metabolic genes (AMGs) and superinfection exclusion, may inadvertently stabilize AMR lineages. Notably, environmental context is shown to govern the shift between kill-the-winner and piggyback-the-winner dynamics, ultimately influencing the efficiency of AMR transfer. This analysis highlights how targeted manipulation of this evolutionary triad could facilitate the development of advanced phage therapeutics and ecological engineering approaches to mitigate global AMR dissemination within the One Health framework.