Canada-Garcia, J. E. | Search bioRxiv

bioRxiv2026

Phage-meropenem synergy against OXA-48-producing Klebsiella pneumoniae clinical isolates

Antimicrobial resistance is a growing global healthcare crisis, driven by the rapid spread of resistant pathogens that compromise existing treatments. Carbapenem-resistant Klebsiella pneumoniae is a major public health threat, requiring novel therapeutic strategies. Phage therapy, which employs phages to target bacterial pathogens, is a promising approach, particularly when combined with antibiotics to enhance efficacy through synergistic interactions. In this study, time-kill curve assays were used to evaluate the synergy between the lytic phage vB_Kpn_2-P4 and meropenem against twelve K. pneumoniae clinical isolates from Spanish hospitals that carried diverse carbapenemases. Notably, in OXA-48-producing isolates, this combination prevented the emergence of resistant mutants, highlighting the therapeutic potential of phage-antibiotic synergy. The observed effect, linked to the presence of the pOXA-48 plasmid, suggests a promising strategy for combating multidrug-resistant bacteria.

microbiology↗

bioRxiv2024

Targeted phage hunting to specific Klebsiella pneumoniae clinical isolates is an efficient antibiotic resistance and infection control strategy

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 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 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 reference Klebsiella spp. serotypes was tested on a panel of carbapenem-resistant K. pneumoniae clinical isolates. 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.

microbiology↗