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Published on: January 7, 2019
A novel phage carrying capsule depolymerase effectively relieves pneumonia caused by multidrug-resistant Klebsiella
Xiaohu Cui1, Bing Du1,2, Junxia Feng1
1Department of Bacteriology, Capital Institute of Pediatrics, Beijing, 100020, China.
Background:
Klebsiella aerogenes can cause ventilator-associated pneumonia by forming biofilms, and it is frequently associated with multidrug resistance. Phages are good antibiotic alternatives with unique advantages. There has been a lack of phage therapeutic explorations, kinetic studies, and interaction mechanism research targeting K. aerogenes.
Methods:
Plaque assay, transmission electron microscopy and whole-genome sequencing were used to determine the biology, morphology, and genomic characteristics of the phage. A mouse pneumonia model was constructed by intratracheal/endobronchial delivery of K. aerogenes to assess the therapeutic effect of phage in vivo. Bioinformatics analysis and a prokaryotic protein expression system were used to predict and identify a novel capsule depolymerase. Confocal laser scanning microscopy, Galleria mellonella larvae infection models and other experiments were performed to clarify the function of the capsule depolymerase.
Results:
A novel lytic phage (pK4-26) was isolated from hospital sewage. It was typical of the Podoviridae family and exhibited serotype specificity, high lytic activity, and high environmental adaptability. The whole genome is 40,234 bp in length and contains 49 coding domain sequences. Genomic data show that the phage does not carry antibiotic resistance, virulence, or lysogenic genes. The phage effectively lysed K. aerogenes in vivo, reducing mortality and alleviating pneumonia without promoting obvious side effects. A novel phage-derived depolymerase was predicted and proven to be able to digest the capsule, remove biofilms, reduce bacterial virulence, and sensitize the bacteria to serum killing.
Conclusions:
The phage pK4-26 is a good antibiotic alternative and can effectively relieve pneumonia caused by multidrug-resistant K. aerogenes. It carries a depolymerase that removes biofilms, reduces virulence, and improves intrinsic immune sensitivity.
Insights
A novel lytic phage, pK4-26, effectively treats Klebsiella aerogenes pneumonia, offering an antibiotic alternative. This phage and its depolymerase reduce biofilms and bacterial virulence, aiding in combating multidrug-resistant infections.
Area of Science:
- Bacteriology
- Virology
- Microbial Pathogenesis
Background:
- Klebsiella aerogenes causes ventilator-associated pneumonia and exhibits multidrug resistance.
- Bacteriophages (phages) present a promising alternative to antibiotics.
- Limited research exists on phage therapeutics, kinetics, and mechanisms against K. aerogenes.
Purpose of the Study:
- To isolate and characterize a novel lytic phage targeting K. aerogenes.
- To evaluate the therapeutic efficacy of the phage and its derived depolymerase against K. aerogenes pneumonia.
- To elucidate the mechanism of action of the phage-derived depolymerase.
Main Methods:
- Isolation and characterization of lytic phage pK4-26 using plaque assays, electron microscopy, and whole-genome sequencing.
- In vivo efficacy assessment in a mouse pneumonia model.
- Bioinformatics analysis and protein expression to identify and characterize a novel capsule depolymerase, with functional validation using microscopy and infection models.
Main Results:
- A novel lytic phage, pK4-26 (Podoviridae family), was isolated, exhibiting high lytic activity and adaptability without antibiotic resistance or virulence genes.
- Phage pK4-26 demonstrated significant therapeutic effects in a mouse pneumonia model, reducing mortality and alleviating symptoms.
- A novel phage-derived depolymerase was identified, capable of degrading bacterial capsules, disrupting biofilms, reducing virulence, and increasing bacterial susceptibility to serum killing.
Conclusions:
- The phage pK4-26 is a viable antibiotic alternative for treating multidrug-resistant K. aerogenes pneumonia.
- The phage's depolymerase plays a crucial role in combating infection by degrading biofilms and reducing bacterial virulence.
- This study highlights the potential of phage therapy and phage-derived enzymes in addressing challenging bacterial infections.
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