Needle in a Whey-Stack: PhRACS as a Discovery Tool for Unknown Phage-Host Combinations

The field of metagenomics has rapidly expanded to become the go-to method for complex microbial community analyses. However, there is currently no straightforward route from metagenomics to traditional culture-based methods of strain isolation, particularly in (bacterio)phage biology, leading to an investigative bottleneck. Here, we describe a method that exploits specific phage receptor binding protein (RBP)-host cell surface receptor interaction enabling isolation of phage-host combinations from an environmental sample. The method was successfully applied to two complex sample types—a dairy-derived whey sample and an infant fecal sample, enabling retrieval of specific and culturable phage hosts.