Phage Therapy as a Novel Alternative to Antibiotics Through Adaptive Evolution and Fitness Trade-Offs

The rapid emergence of antibiotic-resistant bacteria requires solutions that extend beyond conventional antibiotics. Bacteriophages (phages) provide targeted antibacterial action but face two key limitations: (1) their narrow natural host ranges and (2) the rapid emergence of evolved bacterial resistance. This review focuses specifically on evolved resistance and highlights two complementary strategies to overcome it by using phage-adaptive evolution and manipulating bacterial fitness trade-offs. Adaptive evolution accelerates phage/bacteria coevolution under host-mediated and environmental selective pressures such as receptor variability, bacterial resistance mutations, and nutrient limitations, resulting in phages with broader host targeting within resistant populations and enhanced lytic activity. Simultaneously, bacterial resistance to phages often leads to fitness costs, including restored antibiotic susceptibility or reduced virulence. These strategies support the rational design of phage/antibiotic combinations that suppress resistance and enhance therapeutic efficacy. In this review, we clarify the distinction between intrinsic host range limitations and evolved resistance, focusing on how adaptive strategies can specifically counter the latter. We discuss the underlying mechanisms, practical applications, and significance of this approach in clinical, agricultural, and environmental areas.