As rising levels of antibiotic resistance limit treatment options against bacterial infections, phage therapy offers a promising alternative. However, as bacteria and phage have co-evolved for millennia within natural microbial communities, where lytic phages naturally regulate bacterial density, a diverse set of phage resistance mechanisms exist. Here, I explore how the structure of bacteria-phage communities influences the evolution of phage resistance, and how the evolutionary principles which shape these communities may be exploited to improve the rational design of phage therapeutics. Using network analysis to assess how environmental conditions influence the structure of bacteria-phage communities, I showed that imbalances in selection pressure can destabilise bacteria-phage communities and drive phage to extinction. The community structure of microbial communities is underpinned by extensive gene-gene interactions between multiple pairs of co-evolving species. By determining the breadth of cross-resistance individual resistance mutations can promote, I characterised how cross-resistance can structure a collection of phage strains, and how these interactions determine the evolution of multiple resistances. Further, I characterised how this could be exploited to limit the evolution of resistance against phage cocktails, revealing that the evolution of multi-phage resistances are influenced by the order of phage exposure, such that sequential exposure promotes accumulation of multiple strong phage-specific resistances whereas simultaneous exposure to phage pairs promotes weaker resistances. Finally, by comparing the efficacy of phage combinations of increasing diversity, I assessed the relative contributions of phage diversity, functional diversity and cross-resistance structure on the efficacy of phage cocktails. This revealed that functionally diverse phage combinations (i.e. those targeting multiple adsorption receptors) make more effective phage cocktails. These results provide insight into the fundamental evolutionary processes which determine the efficacy of phage cocktails, revealing simple concepts which may be implemented to simplify the rational design of therapeutic phage treatments, such as the maximisation of functional diversity
