Receptors Determine Lytic Phage Host Range in Pseudomonas aeruginosa

Abstract Lytic bacteriophages (phage), viral predators of bacteria, offer a promising solution for treating bacterial infections. However, the narrow host range of phages limits the broad utility of individual phages, making the determinants of phage host range a subject of great interest. Here, we perform a genome-wide association study (GWAS) to identify bacterial genes associated with resistance or susceptibility to two lytic phages, OMKO1 and LPS-5, recently used in a clinical trial for patients with cystic fibrosis (pwCF). We analyzed 80 Pseudomonas aeruginosa clinical isolates collected from pwCF. For OMKO1, genes crucial for infection were associated with biofilm formation, exopolysaccharide synthesis, metabolism, porins, and flagellum assembly. We validate a critical role for flagellum genes in transposon mutagenesis experiments and functional assays. For LPS-5, genes associated with DNA repair, metabolism, and lipopolysaccharide biosynthesis are crucial for infection. We confirme the critical role for LPS/O-antigen in susceptibility to LPS-5. Interestingly, the presence of bacterial genes encoding bacterial defence mechanisms is not predictive of phage susceptibility. Instead, the relative abundance of several known defence elements is associated with the number of temperate phages within bacterial genomes. Together, our findings highlight the central role of receptors in determining phage host range, providing valuable insights for the development of phage-based therapies against bacterial infections.