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

Abstract

Escherichia coli O157:H7 is a globally important foodborne pathogen with implications for food safety. Antibiotic treatment for O157 may potentially contribute to the exacerbation of hemolytic uremic syndrome, and the increasing prevalence of antibiotic-resistant strains necessitates the development of new treatment strategies. In this study, the bactericidal effects and resistance development of antibiotic and bacteriophage monotherapy were compared with those of combination therapy against O157. Experiments involving continuous exposure of O157 to phages and antibiotics, along with genetic deletion studies, revealed that the deletion of glpT and uhpT significantly increased resistance to fosfomycin. Furthermore, we found that OmpC functions as a receptor for the PP01 phage, which infects O157, and FhuA functions as a receptor for the newly isolated SP15 phage, targeting O157. In the glpT and uhpT deletion mutants, additional deletion in ompC , the receptor for the PP01 phage, increased resistance to fosfomycin. These findings suggest that specific phages may contribute to antibiotic resistance by selecting the emergence of gene mutations responsible for both phage and antibiotic resistance. While combination therapy with phages and antibiotics holds promise for the treatment of bacterial infections, careful consideration of phage selection is necessary. IMPORTANCE The combination treatment of fosfomycin and bacteriophages against Escherichia coli O157 demonstrated superior bactericidal efficacy compared to monotherapy, effectively suppressing the emergence of resistance. However, mutations selected by phage PP01 led to enhanced resistance not only to the phage but also to fosfomycin. These findings underscore the importance of exercising caution in selecting phages for combination therapy, as resistance selected by specific phages may increase the risk of developing antibiotic resistance.

Isolation, Characterization, and Complete Genome Sequence of Escherichia Phage KIT06 Which Infects Nalidixic Acid-Resistant Escherichia coli

“…However, E. coli NBRC 3972 and nalidixic acid-resistant E. coli started to grow again at 7 and 10 h post-infection, respectively. These results are similar to those of a previous study on phages SP5 and PP01, which infect E. coli 0157:H7 (ATCC 43888), and an increase in turbidity was observed at approximately 8 h, likely due to the emergence of phage-resistant bacteria [39]. Host bacteria treated with phage KIT06 at MOI 1 regrew earlier than those treated at MOI 0.1, suggesting that a lower concentration of phage suppresses the generation of phageresistant bacteria.…”

Phage Therapy: An Alternative Approach to Combat Multi-drug Resistant Infections in Cystic Fibrosis

“…However, some bacteriophages produce depolymerases, capable of modifying the polysaccharides in the biofilm, thus improving their penetration into the matrix and their effectiveness [86]. Together with the aforementioned phage steering, this evidence supports the potential of combining phage therapy with conventional antibiotics for the treatment of multidrug-resistant infections, as confirmed by several in vitro and in vivo studies [87][88][89][90][91].…”