Selective bacteriophages reduce the emergence of resistant bacteria in the bacteriophage-antibiotic combination therapy

Escherichia coli O157:H7 is a globally important foodborne pathogen that affects food safety. Antibiotic administration against O157:H7 may contribute to the exacerbation of hemolytic uremic syndrome (HUS) and antibiotic-resistant strains increase; therefore, bacteriophage therapy (phage therapy) is considered a useful alternative. In the treatment of resistant bacterial infections, combination therapy with bacteriophages and antibiotics, taking advantage of the benefits of both agents, has been suggested to be effective in inhibiting the emergence of antimicrobial-resistant strains; however, its effectiveness against O157:H7 is not well understood. In this study, we isolated SP015, a phage that infects O157:H7, and compared the combined effect of the bacteriophage and fosfomycin (FOM) with that of the PP01 phage. Genomic analysis revealed that FOM exerts its antibacterial activity through glycerol-3-phosphate transporter (GlpT) and hexose phosphate transporter (UhpT) proteins, and the receptors of PP01 and SP015 phages are the outer membrane protein C (OmpC) and ferrichrome outer membrane transporter protein (FhuA), respectively. Experiments with knockout strains have suggested that FOM also uses OmpC, the receptor for PP01, as a transporter. This may explain why the combination treatment with PP01 resulted in a faster emergence of resistance than the combination treatment with SP015. We propose that phage-antibiotic combination therapy requires careful selection of the phage to be used.