Safety assessment of Staphylococcus phages of the family Myoviridae based on complete genome sequences

Abstract

Staphylococcus phages of the Myoviridae family have a wide host range and potential applications in phage therapy. In this report, safety assessments of these phages were conducted based on their complete genome sequences. The complete genomes of Staphylococcus phages of the Myoviridae family were analyzed, and the Open Reading Frame (ORFs) were compared with a pool of virulence and antibiotic resistance genes using the BLAST algorithm. In addition, the lifestyle of the phages (virulent or temperate) was also confirmed using PHACTS. The results showed that all phages were lytic and did not contain resistance or virulence genes based on bioinformatic analyses, excluding the possibility that they could be vectors for the dissemination of these undesirable genes. These findings suggest that the phages are safe at the genome level. The SceD-like transglycosylase, which is a biomarker for vancomycin-intermediate strains, was widely distributed in the phage genomes. Approximately 70% of the ORFs encoded in the phage genomes have unknown functions; therefore, their roles in the antibiotic resistance and virulence of Staphylococcus aureus are still unknown and require consideration before use in phage therapy.

A Kayvirus Distant Homolog of Staphylococcal Virulence Determinants and VISA Biomarker Is a Phage Lytic Enzyme

“…Phage therapy is a promising alternative to antibiotic therapy to cure infections caused by drug-resistant S. aureus strains [87]. However, each potential therapeutic phage should be well characterized at the structural and functional level before introducing it for wider use, to ensure the safety of therapy [16,17]. Although representatives of Twortvirinae subfamily phages that proved to be effective in curing infections with S. aureus have been characterized at the level of genomic sequence, the function of over half of their genes is unknown [6,17,88,89].…”

“…However, each potential therapeutic phage should be well characterized at the structural and functional level before introducing it for wider use, to ensure the safety of therapy [16,17]. Although representatives of Twortvirinae subfamily phages that proved to be effective in curing infections with S. aureus have been characterized at the level of genomic sequence, the function of over half of their genes is unknown [6,17,88,89]. Of special interest is the tgl gene, whose predicted product is slightly homologous to major surface antigens and virulence factors of S. aureus cells, SceD and IsaA [6].…”

“…The homology of Tgl protein to S. aureus autolysins SceD and IsaA has been a major concern. Cui et al [17] wondered whether S. aureus cells infected with a Kayvirus genus phage and producing Tgl could be less sensitive to vancomycin than non-infected cells. While this danger is irrelevant to normal kayvirus development, which leads to cell lysis, it may be relevant to cases of temporal maintenance of lytic phage genome at a stage of multiplication inhibition in slowly growing or starved bacterial cells, commonly known as pseudolysogeny and associated with the expression of certain phage genes and the loss of phage DNA by some pseudolysogens (see [112,113] and references therein).…”

“…The increased production of S. aureus SceD protein was shown to correlate with hVISA or VISA phenotype [48,83,84] which in turn is associated with vancomycin treatment failure [85,86]. Thus, Cui et al [17] speculated that the expression of staphylococcal phage homologs of SceD during S. aureus infection may increase the minimum inhibitory concentration (MIC) of vancomycin required to treat infection by MRSA. To verify this possibility, we compared the MICs of vancomycin required to inhibit the growth of S. aureus RN4220 expressing the tgl gene from a plasmid with that of RN4220 carrying an empty vector.…”

Analysis host-recognition mechanism of staphylococcal kayvirus ɸSA039 reveals a novel strategy that protects Staphylococcus aureus against infection by Staphylococcus pseudintermedius Siphoviridae phages

“…Staphylococcal Myoviridae phages have a broad host range (Lobocka et al 2012; Cui et al 2017). In particular, kayvirus can infect multiple species of Staphylococcus (Lobocka et al 2012).…”