Klebsiella pneumoniaeis one of the most threatening multi-drug resistant pathogens today, with phage therapy being a promising alternative for personalized treatments. However, the intrinsic capsule diversity inKlebsiellaspp. poses a substantial barrier to phage host range, complicating the development of broad-spectrum phage-based treatments. Here, we have isolated and genomically characterized phages capable of infecting each of the acquired 77 reference serotypes ofKlebsiellaspp.,including capsular types widespread among high-riskK. pneumoniaeclones causing nosocomial infections. We demonstrated the possibility of isolating phages for all capsular types in the collection, revealing high capsular specificity among taxonomically related phages, in contrast to a few phages that exhibited broad-spectrum infection capabilities. To decipher the determinants of the specificity of these phages, we focused on their receptor-binding proteins, with particular attention to depolymerase domains. We also explored the possibility of designing a broad-spectrum phage cocktail based on phages isolated in reference capsular type strains, and determining the ability to lysate relevant clinical isolates. Interestingly, a combination of 12 phages capable of infecting 60% of the referenceKlebsiellaspp. serotypes was tested on a panel of carbapenem-resistantK. pneumoniaeclinical isolates. Our results suggest that in a highly variable encapsulated bacterial host, phage hunting must be directed to the specificKlebsiellaisolates. This work is a step forward in the understanding of the complexity of phage-host interactions, and highlights the importance of implementing precise and phage-specific strategies to treatK. pneumoniaeinfections worldwide.
