Exploring bacteria-phage infection networks

The ability of phage to counter-adapt against bacterial resistance has made them an appealing prospect in the development of phage therapy as an antimicrobial treatment. Many phage therapies are cocktails of multiple phage strains aimed to target a broad range of bacterial targets. Antagonistic co- evolution between bacteria and phage has been studied for many years in a pairwise context, but we know less about the nature of coevolution in a community context and how resistance against a diverse group of phage might evolve. Using a collection of Pseudomonas aeruginosa strains isolated from cystic fibrosis patients and associated lytic phage strains we are exploring the occurrence of cross-resistance, where the evolution of resistance to one phage strain prevents infection by other phage strains. Further, we are investigating the fitness costs associated with varying degrees of cross resistance and the genetic mutations they represent. Utilising bipartite network analysis techniques we have characterised the resistance ranges of 280 spontaneous resistance mutants against 28 lytic phage strains. We have found surprisingly high levels of cross resistance across a broad phylogenetic spectrum of phage strains, and have observed multiple resistance profiles initiated against each phage strain. These results suggest that, although the potential for phage therapy against P. aeruginosa infections is great, we must consider the propensity for development of cross resistance to multiple phage strains, and consider this in the rational design of phage therapy cocktails.