Abstract
Carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged as a severe global health challenge. We isolate and characterize two previously unidentified lytic phages, P24 and P39, with large burst sizes active against ST11 KL64, a major CRKP lineage. P24 and P39 represent species of the genera Przondovirus (Studiervirinae subfamily) and Webervirus (Drexlerviridae family), respectively. P24 and P39 together restrain CRKP growth to nearly 8 h. Phage-resistant mutants exhibit reduced capsule production and decreased virulence. Modifications in mshA and wcaJ encoding capsule polysaccharide synthesis mediate P24 resistance whilst mutations in epsJ encoding exopolysaccharide synthesis cause P39 resistance. We test P24 alone and together with P39 for decolonizing CRKP using mouse intestinal colonization models. Bacterial load shed decrease significantly in mice treated with P24 and P39. In conclusion, we report the characterization of two previously unidentified lytic phages against CRKP, revealing phage resistance mechanisms and demonstrating the potential of lytic phages for intestinal decolonization.
Highlights
Carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged as a severe global health challenge
The two phages represent two species belonging to the genus Przondovirus of the family Autographiviridae and the genus Webervirus of the family Drexlerviridae, respectively
The capsule specificity suggests that the use of the two phages is unlikely to disturb human microflora
Summary
Carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged as a severe global health challenge. We report the characterization of two previously unidentified lytic phages against CRKP, revealing phage resistance mechanisms and demonstrating the potential of lytic phages for intestinal decolonization. Bacteriophages or phages are viruses infecting bacterial hosts They had been used as antibacterial agents for about 20 years prior to the application of antibiotics in human[4,5]. CRKP isolates rapidly developed phage resistance within 4 h, but the two phages in combination could postpone the emergence of phage resistance to nearly 8 h. We analyzed phage-resistant isolates and demonstrate that mutations in the capsule synthesis associated gene mshA and glycosyltransferase-encoding gene epsJ (involving in the exopolysaccharide synthesis) can mediate phage resistance, which have not been reported before. We established mouse CRKP colonization models and applied the phages to decolonize CRKP from the intestinal tract of mice. We found the combination of the two phages can significantly reduce CRKP load in the intestinal tract
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