Genomic analysis links phage susceptibility to the K5 capsule in uropathogenic Escherichia coli

Abstract Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections, which can progress to bloodstream infections, while the increasing prevalence of extended-spectrum β-lactamase (ESBL)-producing strains limits treatment options. Although bacteriophage (phage) therapy is promising, identifying effective phages is resource-intensive. Genomic predictors of phage susceptibility could facilitate phage selection; however, the underlying bacterial traits remain uncharacterized. Here, 49 ESBL-producing UPEC clinical isolates and 42 phages were analysed to investigate bacterial genomic features associated with the phage susceptibility. Independent susceptibility clustering and genome-wide association analyses facilitated identification of K5 capsule biosynthesis genes as shared genomic features associated with susceptibility to specific phage clusters. The K5 strains were broadly susceptible, whereas three strains remained nonsusceptible; genome analysis revealed mutations in capsule biosynthesis genes linked to reduced capsular polysaccharide levels. Phage adsorption assays using the K5 capsule fraction supported the K5 capsule as a receptor for these phage clusters. Furthermore, phages associated with K5 susceptibility were predicted to encode putative depolymerases similar to K5 lyase, extending this mechanism to phages effective against ESBL-producing UPEC. These results support the K5 capsule as a receptor for phages targeting ESBL-producing UPEC and highlight its potential as a predictor of phage susceptibility.