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Integrated analysis of therapeutic efficacy and resistance mechanisms of lytic phages targeting ST218 K57 CR-hvKp

ABSTRACT: Clinical infection caused by carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is gradually increasing and spreading across the world, and phage therapy is a viable application as an alternative to antibiotics. However, additional clinical application is still restricted by the phage resistance. In order to further explore the mechanism of phage resistance, particularly the difference between in vivo and in vitro. Here, we used a mouse intra-abdominal infection (IAI) model to evaluate the antibacterial properties of two lytic phages and further isolated and characterized phage-resistant mutants. Finally, we determined through genomic and transcriptomic analysis that most of the mutation sites in the resistant mutants were located in the capsular polysaccharides gene cluster. However, RM01 and RM12 developed phage resistance by downregulating capsular polysaccharide (CPS) and its transcriptional regulators without any mutations in the CPS gene. In summary, these findings provided further evidence in phage therapy, particularly in addressing the issue of CR-hvKP infections.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS12480 | MetaboLights | 2025-09-18

REPOSITORIES: MetaboLights

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Project description:Inhibition of fungal growth by Congo Red (CR) has been known for a long time and claimed to be associated to a specific binding to fibrillar chains of β-1,3-glucans which blocks cell wall polysaccharide synthesis. It has also been suggested that the effect of CR could be pleiotropic, especially because of its oxido-reductive properties. One way to elucidate the mechanism of action of CR is to identify transcription factors (TF) which regulate the response to CR and interrogate their regulon. The analysis of TF mutants with differential sensitivity to CR would be also a way to identify new regulatory pathways involved in cell wall biosynthesis. During the investigation of the sensitivity to CR of a TF mutant library, several mutants either sensitive or resistant to CR were analysed . The morphology of the conidial germination was affected differently by CR in the parental strain and TF mutants. Abnormal distorted swollen conidia called Quasimodo cells were seen in presence of the CR. The size of the Quasimodo cells in the resistant mutants are bigger and adsorb more CR than the germinating conidia of the sensitive or parental strain. This is associated to a difference in permeability of the mutants. The clearing of the drug from the medium by the resistant strain was mainly responsible for the survival and later growth of some of resting conidia of these mutants which did not adsorb intracellularly the drug whereas in the sensitive mutants all conidia adsorbed the drug and were consequently killed. Although there are some modifications of the composition of the cell wall, a transcriptomic analysis of the mutant showed that CR affected many different pathways, including iron and calcium metabolism. Accordingly, the susceptibility to other cell wall drugs of the sensitive and the resistant TF mutants varied with the mutants and not always in connexion with their sensitivity to CR. Interestingly, a new paradoxical effect of the CR was discovered in the resistant mutant since the growth of one of them could be stimulated after recovering from the CR stress.

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Integrated analysis of therapeutic efficacy and resistance mechanisms of lytic phages targeting ST218 K57 CR-hvKp

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