The Right Dose, the Right Host: Effects of Amplification Host and Phage Influx on Efficacy and Coevolution in Pseudomonas aeruginosa

Abstract

Antibiotic resistance poses an increasingly urgent global health threat, driving rising mortality and healthcare costs worldwide. Bacteriophages, viruses that infect and lyse bacterial cells, have garnered significant interest as potential replacements or complements to antibiotics. A critical step in clinical use of phages, known as phage therapy, is the amplification of phage particles on a susceptible host strain prior to therapeutic use. Yet the impact of amplification host strain identity on phage phenotype remains poorly characterized. Furthermore, the repeated dosing of phage into already-coevolving bacterial populations during treatment has potential implications for resistance trajectories that are not well understood. Using Pseudomonas aeruginosa and the lytic phage ΦPA3 as a model system, this study demonstrates that amplification host strain identity modulates phage host range and killing efficacy, with exopolysaccharide content implicated as a potential mechanistic source of this modulation. A mathematical model of bacteria-phage coevolution additionally demonstrates that repeated phage influx accelerates the extinction of susceptible bacteria, but that this effect does not scale with increasing daily dose frequency, suggesting diminishing returns beyond a single daily administration. Together, these findings highlight amplification host identity as a biologically meaningful variable in phage therapy design, and suggest that dosing frequency may have less influence on resistance evolution than previously assumed.