Abstract
Proteus mirabilis often complicates the care of catheterized patients through the formation of crystalline biofilms which block urine flow. Bacteriophage therapy has been highlighted as a promising approach to control this problem, but relatively few phages infecting P. mirabilis have been characterized. Here we characterize five phages capable of infecting P. mirabilis, including those shown to reduce biofilm formation, and provide insights regarding the wider ecological and evolutionary relationships of these phages. Transmission electron microscopy (TEM) imaging of phages vB_PmiP_RS1pmA, vB_PmiP_RS1pmB, vB_PmiP_RS3pmA, and vB_PmiP_RS8pmA showed that all share morphologies characteristic of the Podoviridae family. The genome sequences of vB_PmiP_RS1pmA, vB_PmiP_RS1pmB, and vB_PmiP_RS3pmA showed these are species of the same phage differing only by point mutations, and are closely related to vB_PmiP_RS8pmA. Podophages characterized in this study were also found to share similarity in genome architecture and composition to other previously described P. mirabilis podophages (PM16 and PM75). In contrast, vB_PimP_RS51pmB showed morphology characteristic of the Myoviridae family, with no notable similarity to other phage genomes examined. Ecogenomic profiling of all phages revealed no association with human urinary tract viromes, but sequences similar to vB_PimP_RS51pmB were found within human gut, and human oral microbiomes. Investigation of wider host-phage evolutionary relationships through tetranucleotide profiling of phage genomes and bacterial chromosomes, indicated vB_PimP_RS51pmB has a relatively recent association with Morganella morganii and other non-Proteus members of the Morganellaceae family. Subsequent host range assays confirmed vB_PimP_RS51pmB can infect M. morganii.
Highlights
The opportunistic pathogen Proteus mirabilis is a common cause of catheter-associated urinary tract infections (CAUTIs) and can significantly complicate the care of patients undergoing long-term urethral catheterization (Mobley, 1996; Stickler, 2008, 2014)
Phages capable of infecting P. mirabilis were isolated from sewage using clinical isolates of P. mirabilis recovered from urinary tract infections
Phages were initially characterized based on plaque and virion morphology and compared to previously isolated phages (Proteus_phage_vB_PmiP_RS1pmA, RS1pmB, and RS3pmA), which have been shown to reduce P. mirabilis crystalline biofilm formation when tested in vitro infection models (Nzakizwanayo et al, 2016)
Summary
The opportunistic pathogen Proteus mirabilis is a common cause of catheter-associated urinary tract infections (CAUTIs) and can significantly complicate the care of patients undergoing long-term urethral catheterization (Mobley, 1996; Stickler, 2008, 2014). The blockage of catheters by P. mirabilis is derived from the ability of this organism to form dense biofilms on the surface of catheters, in conjunction with the production of a potent urease enzyme (Griffith et al, 1976; Jones and Mobley, 1987; Stickler et al, 1993; Jones et al, 2005) This highly active enzyme hydrolyses urea present in the urine and generates ammonia, which in turn elevates urinary pH (Hedelin et al, 1984; Cox and Hukins, 1989; Stickler et al, 1993; Holling et al, 2014a,b). As the biofilm continues to develop, these crystals become trapped in the growing community, where the exopolymeric matrix further stabilizes and enhances their growth, eventually leading to the development of a mineralized crystalline biofilm structure that can block urine flow (Stickler et al, 1993; Stickler, 2008)
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