The Host R‐M Systems Change the Host Range of <i>Staphylococcus</i> Phage EBHT

Therapeutically utilized phages should optimally be produced in defined bacterial strains that are free of prophages and virulence factors. However, phage-host interactions in these production strains may be very different from clinical strains. Here, we characterized a lytic Staphylococcus aureus-specific phage vB_SauP_EBHT (EBHT), which had a dramatic change in its host specificity when produced in alternative host 19A2 compared with the original isolation host DSM 104437, even though there were no changes in the phage genome, proteome, structure, or adsorption efficiency. The reason for the altered host range was revealed to be based on different methylation patterns of the EBHT genome by host restriction-modification (R-M) systems in the two hosts. Even though the alternative host 19A2 produced a higher burst size, the host range of the produced phages was narrower. Together, these results illustrate that the most efficient production host may not necessarily be the most optimal one and that bacterial R-M systems should be considered when selecting the optimal phage-production host.