The Ability of Lytic Staphylococcal Podovirus vB_SauP_phiAGO1.3 to Coexist in Equilibrium With Its Host Facilitates the Selection of Host Mutants of Attenuated Virulence but Does Not Preclude the Phage Antistaphylococcal Activity in a Nematode Infection Model

Abstract

Phage vB_SauP_phiAGO1.3 (phiAGO1.3) is a polyvalent <i>Staphylococcus</i> lytic podovirus with a 17.6-kb genome (Gozdek et al., 2018). It can infect most of the <i>Staphylococcus aureus</i> human isolates of dominant clonal complexes. We show that a major factor contributing to the wide host range of phiAGO1.3 is a lack or sparcity of target sites for certain restriction-modification systems of types I and II in its genome. Phage phiAGO1.3 requires for adsorption β-<i>O</i>-GlcNAcylated cell wall teichoic acid, which is also essential for the expression of methicillin resistance. Under certain conditions an exposure of <i>S. aureus</i> to phiAGO1.3 can lead to the establishment of a mixed population in which the bacteria and phages remain in equilibrium over multiple generations. This is reminiscent of the so called phage carrier state enabling the co-existence of phage-resistant and phage-sensitive cells supporting a continuous growth of the bacterial and phage populations. The stable co-existence of bacteria and phage favors the emergence of phage-resistant variants of the bacterium. All phiAGO1.3-resistant cells isolated from the phage-carrier-state cultures contained a mutation inactivating the two-component regulatory system ArlRS, essential for efficient expression of numerous <i>S. aureus</i> virulence-associated traits. Moreover, the mutants were unaffected in their susceptibility to infection with an unrelated, polyvalent <i>S. aureus</i> phage of the genus <i>Kayvirus</i>. The ability of phiAGO1.3 to establish phage-carrier-state cultures did not preclude its antistaphylococcal activity <i>in vivo</i> in an <i>S. aureus</i> nematode infection model. Taken together our results suggest that phiAGO1.3 could be suitable for the therapeutic application in humans and animals, alone or in cocktails with <i>Kayvirus</i> phages. It might be especially useful in the treatment of infections with the majority of methicillin-resistant <i>S. aureus</i> strains.