A novel broad host range phage phiA85 displays a synergistic effect with antibiotics targeting carbapenem-resistant Klebsiella pneumoniae.

UNLABELLED: Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a major public health threat worldwide due to the limited treatment options available. There is an urgent need to explore new treatment strategies. Although phages are considered to be an effective treatment, most characterized Klebsiella phages demonstrate narrow host ranges restricted to specific capsular types (KL types), thereby limiting their clinical applicability. In the present study, we isolated a novel broad host range phage, phiA85, with high lytic activity and biofilm inhibitory efficacy against host strains of 13 different KL types and 12 ST types. Among these host strains, six strains were identified as multidrug-resistant (MDR)-CRKP covering five different KL types. To further optimize phage therapy, this study indicated that phage phiA85 in combination with sublethal concentrations of antibiotics had synergistic effects against CRKP in vitro and in vivo. Killing curves and biofilm quantification assays revealed that phiA85-imipenem and phiA85-ciprofloxacin combinations exhibited phage-antibiotic synergy (PAS), demonstrating better bactericidal efficacy and reduction in biofilm formation compared to monotherapy. In a mouse pneumonia model, phage phiA85-imipenem combination treatment reduced mortality and alleviated pneumonia without other side effects. Our findings identify a broad host range phage capable of lysing different KL types and ST types of K. pneumoniae. Notably, phage phiA85-antibiotic combination offers a promising therapeutic option for the clinical treatment against MDR-CRKP.

IMPORTANCE: The widespread prevalence of MDR bacteria has become a critical public health threat with limited therapeutic options. This study identifies a novel broad host range phage phiA85, capable of lysing strains across different KL types of CRKP. This characteristic addresses the limitation of narrow host range of capsular-specific phages, thereby significantly expanding their therapeutic potential against multidrug-resistant bacterial infections. Phage phiA85-antibiotic combinations achieve PAS, enhancing lytic activity and biofilm inhibition in vitro and alleviating mouse pneumonia. These findings highlight that phage phiA85-antibiotic combinations are a promising strategy to combat MDR-CRKP infections. Our work provides critical insights into optimizing phage therapy for clinical use against priority pathogens.