Lytic bacteriophages (phages) are natural viral predators of bacteria and can be useful alternatives to antibiotics to combat multidrug resistant infections [1]. Phages can be highly successful targeted antimicrobials in vitro. However, preference for a specific bacterial host (narrow host range) and resistance development are significant barriers to the routine implementation of phage therapy and prediction of clinical (in vivo) efficacy. A better understanding of the outcomes of dynamic phage-bacteria interactions in vivo is required to make significant progress towards effective therapeutic use of phages.
Towards this goal, we have: 1) characterized a comprehensive set of phages against a major pathogenic clone, Escherichia coli ST131, which causes severe extra-intestinal infections in humans including sepsis [2], 2) developed murine models of gut colonization and of severe infection (bacteraemia), and 3) tested the efficacy of a four-phage combination in these models.
Data on bacterial clearance and phage kinetics in our murine sepsis model showed how in vitro clearance does not immediately correlate with in vivo outcomes, pointing to different co-adaptation patterns related to the complexity of in vivo niches. The colonization model allowed us to test the effect of prolonged in vivo co-incubation of target E. coli with these phages in the gut. A steady-state rapidly evolved between the two bacterial populations with co-existence over time (6 weeks) correlated with complex patterns of bacterial resistance development. The genomes of the E. coli recovered from the faeces and organs of the treated mice were not significantly different to that of the parent strain, indicating more complex underlying resistance mechanisms than genetic mutation.
Our work shows that the in vivo response of bacterial populations to attacking phages is complex and needs to be fully explored in order to be able to exploit the full therapeutic potential of these microorganisms.