Abstract
Alternative treatments for Escherichia coli infections are urgently needed, and phage therapy is a promising option where antibiotics fail, especially for urinary tract infections (UTI). We used wastewater-isolated phages to test their lytic activity against a panel of 47 E. coli strains reflecting the diversity of strains found in UTI, including sequence type 131, 73 and 69. The plaquing host range (PHR) was between 13 and 63%. In contrast, the kinetic host range (KHR), describing the percentage of strains for which growth in suspension was suppressed for 24 h, was between 0% and 19%, substantially lower than the PHR. To improve the phage host range and their efficacy, we bred the phages by mixing and propagating cocktails on a subset of E. coli strains. The bred phages, which we termed evolution-squared ε2-phages, of a mixture of Myoviridae have KHRs up to 23% broader compared to their ancestors. Furthermore, using constant phage concentrations, Myoviridae ε2-phages suppressed the growth of higher bacterial inocula than their ancestors did. Thus, the ε2-phages were more virulent compared to their ancestors. Analysis of the genetic sequences of the ε2-phages with the broadest host range reveals that they are mosaic intercrossings of 2–3 ancestor phages. The recombination sites are distributed over the whole length of the genome. All ε2-phages are devoid of genes conferring lysogeny, antibiotic resistance, or virulence. Overall, this study shows that ε2-phages are remarkably more suitable than the wild-type phages for phage therapy.
Highlights
Uncomplicated urinary tract infections (UTI), which are caused predominantly by uropathogenic Escherichia coli (UPEC) are amongst the most common reasons for medical consultation [1]
Twenty-eight phages showing clear plaques with activity against E. coli strains were selected for further characterization
We examined the growth of a subset of 22 of the 47 UPEC strains (Table S2) in the presence of selected ε2-phages at different multiplicities of infection (MOI)
Summary
Uncomplicated urinary tract infections (UTI), which are caused predominantly by uropathogenic Escherichia coli (UPEC) are amongst the most common reasons for medical consultation [1]. Several international studies performing DNA profiling revealed the predominance of the sequence types (ST) 69, 73, 95, and 131, among others, in isolates from patients with UTI [2,3,4,5,6,7]. These STs differ markedly in their antibiotic resistance profiles. Due to the increasing rates of resistance of uropathogens against cotrimoxazole, fluoroquinolones, and β-lactams, these classical oral antibiotics cannot be used for empiric therapy any more in many geographic regions [10,11]. To counteract the increasing resistance rates, alternative treatment options need to be investigated
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