Biological and bioinformatic tools for the discovery of unknown phage–host combinations

The field of microbial ecology has been transformed by metagenomics in recent decades and has culminated in vast datasets that facilitate the bioinformatic dissection of complex microbial communities. Recently, attention has turned from defining the microbiota composition to the interactions and relationships that occur between members of the microbiota. Within complex microbiota, the identification of bacteriophage–host combinations has been a major challenge. Recent developments in artificial intelligence tools to predict protein structure and function as well as the relationships between bacteria and their infecting bacteriophages allow a strategic approach to identifying and validating phage–host relationships. However, biological validation of these predictions remains essential and will serve to improve the existing predictive tools. In this review, I provide an overview of the most recent developments in both bioinformatic and experimental approaches to predicting and experimentally validating unknown phage–host combinations.