Building reusable phage and antibiotic treatments via exploitation of bacteria-phage coevolutionary dynamics

People with chronic (long-lasting) infections face the problem that treatment options diminish in time as the pathogen evolves increasing resistance. To address this challenge, we exploit phage and bacterial co-evolution, producing dynamic selection pressures that can return the pathogen to a state of susceptibility to the initial (regulator-approved) therapy. We show that phage OMKO1 alone triggers Arms Race Dynamic (ARD) co-evolution with the pathogen Pseudomonas aeruginosa , leading to generalized phage resistance and crucially – failure at reuse. In contrast, co-administration of the phage with antibiotics triggers Fluctuating Selection Dynamics (FSD) co-evolution, allowing for effective reuse after 20 days of treatment. We pursue medical relevance in our experiments with the use of clinically important pathogens, antibiotics, phage, and a benchmarked synthetic sputum medium. Phenotypic and genomic characterization of evolved isolates demonstrates that efflux-targeting phage OMKO1 exerts continued selection for antibiotic susceptibility regardless of co-evolutionary dynamic or antibiotic co-treatment, opening the door for evolutionary robust phage therapy.