Anti-phage defence systems are enriched in multidrug-resistant Pseudomonas aeruginosa

Pseudomonas aeruginosa encodes diverse defence systems against phages and mobile genetic elements, yet their variation across clinical contexts remains unclear. Here, we present a large-scale comparative analysis of the P. aeruginosa defensome across both public and clinically highly relevant datasets, including from patients with chronic lung disease and multidrug-resistant isolates. Our analysis shows that while influences on defensome composition are minor, multidrug-resistant isolates encode more defence systems and cystic fibrosis-associated isolates have fewer. Across phylogenetic clusters, defensome size correlates with cluster abundance, suggesting that defence rich lineages persist more successfully across environments. Lastly, comparative analysis with other Pseudomonas species reveals enrichment of anti-plasmid systems in P. aeruginosa. Overall, these findings have important implications for phage therapy: multidrug resistant infections may be more difficult to treat, while cystic-fibrosis-associated isolates may have higher phage susceptibility. This work provides a framework for understanding defensome variation and guiding the decision-making process of phage-based therapies.