Abstract
Phage vB_SauP_phiAGO1.3 (phiAGO1.3) is a polyvalent Staphylococcus lytic podovirus with a 17.6-kb genome (Gozdek et al., 2018). It can infect most of the Staphylococcus aureus 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-O-GlcNAcylated cell wall teichoic acid, which is also essential for the expression of methicillin resistance. Under certain conditions an exposure of S. aureus 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 S. aureus virulence-associated traits. Moreover, the mutants were unaffected in their susceptibility to infection with an unrelated, polyvalent S. aureus phage of the genus Kayvirus. The ability of phiAGO1.3 to establish phage-carrier-state cultures did not preclude its antistaphylococcal activity in vivo in an S. aureus 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 Kayvirus phages. It might be especially useful in the treatment of infections with the majority of methicillin-resistant S. aureus strains.
Highlights
Staphylococcus aureus is among the most challenging bacterial pathogens that cause various types of infections mainly in humans and in animals (Springer et al, 2009; Otto, 2012)
Selected obligatorily lytic bacteriophages that efficiently kill bacterial pathogens may become the option of choice in the treatment of infections with antibiotic-resistant bacterial strains
We show that the polyvalent staphylococcal lytic podovirus phiAGO1.3 has properties that make it a potential candidate for therapeutic applications, identify factors that contribute to its wide strain range, and prove its therapeutic efficacy in curing a staphylococcal infection of a model nematode, Caenorhabditis elegans
Summary
Staphylococcus aureus is among the most challenging bacterial pathogens that cause various types of infections mainly in humans and in animals (Springer et al, 2009; Otto, 2012). The limitation of effective MRSA treatment options with antibiotics often leads to the development of chronic infections and is a cause of increased mortality, longer hospital stays and higher health care costs as compared to methicillin-sensitive S. aureus (MSSA) strains (Cosgrove et al, 2003; de Kraker et al, 2011). One of the alternative approaches to curing infections with antibiotic-resistant S. aureus strains is the use of lytic bacteriophages (Borysowski et al, 2011; Kazmierczak et al, 2014). These are natural parasites of bacteria that can infect and kill their host but are harmless to eukaryotic cells. Numerous cases of successful treatment of S. aureus infections with bacteriophages in animals (Iwano et al, 2018; reviewed by Barrera-Rivas et al, 2017) and in humans (d’Herelle, 1931a,b; MacNeal and Frisbee, 1936a,b; Sauve, 1936; Miedzybrodzki et al, 2012; Fadlallah et al, 2015; Fish et al, 2016; reviewed by Kazmierczak et al, 2014) have been described
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