Whole-Genome Analysis Reveals That Bacteriophages Promote Environmental Adaptation of <i>Staphylococcus aureus</i> via Gene Exchange, Acquisition, and Loss

The study of bacteriophages is experiencing a resurgence owing to their antibacterial efficacy, lack of side effects, and low production cost. Nonetheless, the interactions between <i>Staphylococcus aureus</i> bacteriophages and their hosts remain unexplored. In this study, whole-genome sequences of 188 <i>S. aureus</i> bacteriophages—20 <i>Podoviridae</i>, 56 <i>Herelleviridae</i>, and 112 <i>Siphoviridae</i>—were obtained from the National Center for Biotechnology Information (NCBI, USA) genome database. A phylogenetic tree was constructed to estimate their genetic relatedness using single-nucleotide polymorphism analysis. Comparative analysis was performed to investigate the structural diversity and ortholog groups in the subdividing clusters. Mosaic structures and gene content were compared in relation to phylogeny. Phylogenetic analysis revealed that the bacteriophages could be distinguished into three lineages (I–III), including nine subdividing clusters and seven singletons. The subdividing clusters shared similar mosaic structures and core ortholog clusters, including the genes involved in bacteriophage morphogenesis and DNA packaging. Notably, several functional modules of bacteriophages 187 and 2368A shared more than 95% nucleotide sequence identity with prophages in the <i>S. aureus</i> strain RJ1267 and the <i>Staphylococcus pseudintermedius</i> strain SP_11306_4, whereas other modules exhibited little nucleotide sequence similarity. Moreover, the cluster phages shared similar types of holins, lysins, and DNA packaging genes and harbored diverse genes associated with DNA replication and virulence. The data suggested that the genetic diversity of <i>S. aureus</i> bacteriophages was likely due to gene replacement, acquisition, and loss among staphylococcal phages, which may have crossed species barriers. Moreover, frequent module exchanges likely occurred exclusively among the subdividing cluster phages. We hypothesize that during evolution, the <i>S. aureus</i> phages enhanced their DNA replication in host cells and the adaptive environment of their host.