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.