Targeted phage hunting to specific
Klebsiella pneumoniae
clinical isolates is an efficient antibiotic resistance and infection control strategy
Authors: Ferriol-González Celia , Concha-Eloko Robby , Bernabéu-Gimeno Mireia , Fernández-Cuenca Felipe , Cañada-García Javier E. , García-Cobos Silvia , Sanjuán Rafael , Domingo-Calap Pilar 
Published: August 2024

ABSTRACT

Klebsiella pneumoniae
is 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 in
Klebsiella
spp. poses a substantial barrier to the 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 of
Klebsiella
spp.
,
including capsular types widespread among high-risk
K. pneumoniae
clones 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 depolymerases. 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 lyse relevant clinical isolates. A combination of 12 phages capable of infecting 55% of the reference
Klebsiella
spp. serotypes was tested on a panel of carbapenem-resistant
K. pneumoniae
clinical isolates. Thirty-one percent of isolates were susceptible to the phage cocktail. However, our results suggest that in a highly variable encapsulated bacterial host, phage hunting must be directed to the specific
Klebsiella
isolates. 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 treat
K. pneumoniae
infections worldwide.

IMPORTANCE

The emergence of resistant bacteria is a serious global health problem. In the absence of effective treatments, phages are a personalized and effective therapeutic alternative. However, little is still known about phage–host interactions, which are key to implementing effective strategies. Here, we focus on the study of
Klebsiella pneumoniae,
a highly pathogenic encapsulated bacterium. The complexity and variability of the capsule, where in most cases phage receptors are found, make it difficult for phage-based treatments. Here, we isolated a large collection of
Klebsiella
phages against all the reference strains and in a cohort of clinical isolates. Our results suggest that clinical isolates represent a challenge, especially high-risk clones. Thus, we propose targeted phage hunting as an effective strategy to implement phage-derived therapies. Our results are a step forward for new phage-based strategies to control
K. pneumoniae
infections, highlighting the importance of understanding phage–host interactions to design personalized treatments against
Klebsiella
spp.