Parallel evolution of phage resistance - virulence trade - offs duringin vitroand nasalPseudomonas aeruginosaphage treatment

With rising antibiotic resistance, there has been increasing interest in treating pathogenic bacteria with bacteriophages (phage therapy). One limitation of phage therapy is the ease at which bacteria can evolve resistance. Negative effects of resistance may be mitigated when resistance results in reduced bacterial growth and virulence, or when phage coevolve to overcome resistance. Resistance evolution and its consequences are contingent on the bacteria-phage combination and their environmental context, making therapeutic outcomes hard to predict. One solution might be to conduct “in vitroevolutionary simulations” using bacteria-phage combinations from the therapeutic context. Overall, our aim was to investigate parallels betweenin vitroexperiments andin vivodynamics in a human participant. Evolutionary dynamics were similar, with high levels of resistance evolving quickly with limited evidence of phage evolution. Resistant bacteria – evolvedin vitroandin vivo- had lower virulence.In vivo, this was linked to lower growth rates of resistant isolates, whereasin vitrophage resistant isolates evolved greater biofilm production. Population sequencing suggests resistance resulted from selection onde novomutations rather than sorting of existing variants. These results highlight the speed at which phage resistance can evolvein vivo, andin vitroexperiments may give useful insights for clinical evolutionary outcomes.