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Evolution of virulence in Klebsiella pneumoniae treated with phage cocktails
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The worldwide emergence and spread of multidrug-resistant bacteria is a major concern in modern medicine, and threatens the once established control over bacterial infections. Phage therapy has been suggested as one potential solution to the problem of finding new antibacterial agents. Bacteria are known to evolve resistance against bacteriophages but in many cases phage-resistance comes with a cost on bacterial virulence in multicellular hosts. We investigated how the virulence of a clinical isolate of K. pneumoniae Kpn524 evolves in response to exposure to phage cocktails in the phage-resistant bacteria that would potentially survive the phage treatment. We found that the exposure to multiple phages was linked to lowered virulence in the phage-resistant bacteria, when measured in vivo with Galleria mellonella. However, two phages were found to increase the bacterial virulence when they were administered on the bacteria individually, and this was associated with an increased growth rate. Across all treatments, biofilm production was negatively correlated with virulence, whereas growth rate had a positive correlation with bacterial virulence. Our findings suggest that bacterial virulence is attenuated in the presence of multiple phages, possibly due to a trade-off between phage resistance andrate of replication. However, this is dependent on the composition of the phage cocktail.This is the first study to report increased bacterial virulence associated with exposure tolytic bacteriophages and our results call for meticulous consideration when choosingphages for phage cocktails, as phages with certain identity could have detrimentally adverse effects on the success of the treatment.

National Category
Evolutionary Biology Genetics Microbiology
Research subject
Molecular Genetics
URN: urn:nbn:se:su:diva-115902OAI: diva2:800967
Available from: 2015-04-08 Created: 2015-04-08 Last updated: 2016-01-29Bibliographically approved
In thesis
1. Bacterial viruses targeting multi-resistant Klebsiella pneumoniae and Escherichia coli
Open this publication in new window or tab >>Bacterial viruses targeting multi-resistant Klebsiella pneumoniae and Escherichia coli
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The global increase in antibiotic resistance levels in bacteria is a growing concern to our society and highlights the need for alternative strategies to combat bacterial infections. Bacterial viruses (phages) are the natural predators of bacteria and are as diverse as their hosts, but our understanding of them is limited. The current levels of knowledge regarding the role that phage play in the control of bacterial populations are poor, despite the use of phage therapy as a clinical therapy in Eastern Europe.

The aim of this doctoral thesis is to increase knowledge of the diversity and characteristics of bacterial viruses and to assess their potential as therapeutic agents towards multi-resistant bacteria.

Paper I is the product of de novo sequencing of newly isolated phages that infect and kill multi-resistant Klebsiella pneumoniae. Based on similarities in gene arrangement, lysis cassette type and conserved RNA polymerase, the creation of a new phage genus within Autographivirinae is proposed.

Paper II describes the genomic and proteomic analysis of a phage of the rare C3 morphotype, a Podoviridae phage with an elongated head that uses multi-resistant Escherichia coli as its host.

Paper III describes the study of a pre-made phage cocktail against 125 clinical K. pneumoniae isolates. The phage cocktail inhibited the growth of 99 (79 %) of the bacterial isolates tested. This study also demonstrates the need for common methodologies in the scientific community to determine how to assess phages that infect multiple serotypes to avoid false positive results.

Paper IV studies the effects of phage predation on bacterial virulence: phages were first allowed to prey on a clinical K. pneumoniae isolate, followed by the isolation of phage-resistant bacteria. The phage resistant bacteria were then assessed for their growth rate, biofilm production in vitro. The virulence of the phage resistant bacteria was then assessed in Galleria mellonella. In the single phage treatments, two out of four phages showed an increased virulence in the in G. mellonella, which was also linked to an increased growth rate of the phage resistant bacteria. In multi-phage treatments however, three out of five phage cocktails decreased the bacterial virulence in G. mellonella compared to an untreated control.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2015. 49 p.
Bacterial viruses, Bacteriophage, Phage, Phage therapy, multi-resistant bacteria, Klebsiella pneumoniae
National Category
Research subject
Molecular Genetics
urn:nbn:se:su:diva-116711 (URN)978-91-7649-123-2 (ISBN)
Public defence
2015-05-29, sal E306, Arrheniuslaboratorierna, Svante Arrhenius väg 20C, Stockholm, 10:00 (English)

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.

Available from: 2015-05-07 Created: 2015-04-23 Last updated: 2015-06-23Bibliographically approved

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Eriksson, HaraldNilsson, Anders
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