A comprehensive phage-bacteria interaction atlas links phage lineage and capsule serotype to genome-guided machine learning prediction in <i>Klebsiella pneumoniae</i>

<jats:p> <jats:italic>Klebsiella pneumoniae</jats:italic> is a WHO critical-priority pathogen for which strain-specific bacteriophages are being explored as precision antimicrobials, yet rapid phage-host matching remains a major barrier to therapeutic deployment. We constructed a comprehensive interaction atlas comprising 84 taxonomically diverse phages and 101 globally sourced, clinically representative <jats:italic>K. pneumoniae</jats:italic> strains, including multidrug-resistant isolates. Systematic pairwise profiling produced 8,484 interaction measurements, of which 2,656 (31.3%) scored positive for bacterial clearance. Genus was the dominant phage-side determinant of host range, while capsule K-serotype was the strongest host-side determinant of susceptibility; aggregate defense, prophage, plasmid, and antimicrobial-resistance features contributed comparatively little. A genome-guided machine learning model predicted interactions without curated host annotations (AUROC, 0.882; AUPR, 0.765), outperforming a model based only on phage genus and K-serotype and modestly exceeding a curated genomic baseline. The model recovered capsule- and lipopolysaccharide-biosynthesis genes, canonical receptors and defense-associated features as major predictors using SHAP analysis. Feasibility tests of expert- and model-selected cocktails exposed a translational constraint. Although all formulations suppressed growth <jats:italic>in vitro</jats:italic> , only the specific cocktail whose phages replicated robustly within the murine gut reduced colonization, suggesting <jats:italic>in vivo</jats:italic> amplification rather than predicted host range as the limiting factor for therapeutic efficacy. Together with the activity of a model-selected cocktail built for an isolate completely excluded from training, these results provide a species-wide resource for <jats:italic>K. pneumoniae</jats:italic> phage matching and support a hybrid workflow combining genome-based ranking with targeted phenotypic validation. </jats:p>