Overcoming the growth-infectivity trade-off in a bacteriophage slows bacterial resistance evolution

The use of lytic bacteriophages for treating harmful bacteria (phage therapy) is faced with the challenge of bacterial resistance evolution. Phage strains with certain traits, for example, rapid growth and relatively broad infectivity ranges, may enjoy an advantage in slowing bacterial resistance evolution. Here, we show the possibility for laboratory selection programs ("evolutionary training") to yield phage genotypes with both high growth rate and broad infectivity, traits between which a trade-off has been assumed. We worked with a lytic phage that infects the bacterium Pseudomonas fluorescens and adopted three types of training strategies: evolution on susceptible bacteria, coevolution with bacteria, and rotation between evolution and coevolution phases. Overall, there was a trade-off between growth rate and infectivity range in the evolved phage isolates, including those from the rotation training programs. A small number of phages had both high growth rate and broad infectivity, and those trade-off-overcoming phages could slow or even completely prevent resistance evolution in initially susceptible bacterial populations. Our findings show the promise of well-designed evolutionary training programs, in particular an evolution/coevolution rotation selection regime, for obtaining therapeutically useful phage materials.