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A novel phage cocktail inhibiting the growth of 99 β-lactamase carrying Klebsiella pneumoniae clinical isolates in vitro
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Klebsiella pneumoniae is a gram-negative bacterial pathogen, accountable for a variety of nosocomial infections in immunocompromised patients, open-wound infections and community-acquired pneumonia in elderly. K. pneumoniae strains harboring plasmid-mediated extended spectrum β-lactamase enzymes (ESBL) are resistant to all penicillin and cephalosoprins, whereas bacteria capable of producing carbapenemase enzymes (e.g. NDM, KPC and VIM) are resistant to virtually all β-lactam group antibiotics. The use of bacterial viruses lysing bacterial hosts (phage therapy) has been suggested as an alternative in fighting bacterial infections resistant to known antibiotics. In this study, we assembled a phage cocktail consisting of 6 novel lytic bacteriophages infecting K. pneumoniae. The phage cocktail was tested against 125 β-lactamase producing clinical isolates of K. pneumoniae and we found that at high titres, the cocktail was able to lyse 99 of these isolates in vitro.

Keyword [en]
Phage therapy, Klebsiella pneumoniae, Lytic phage, ESBL, Phage cocktail
National Category
Microbiology
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-115898OAI: oai:DiVA.org:su-115898DiVA: diva2:800951
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.
Keyword
Bacterial viruses, Bacteriophage, Phage, Phage therapy, multi-resistant bacteria, Klebsiella pneumoniae
National Category
Genetics
Research subject
Molecular Genetics
Identifiers
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)
Opponent
Supervisors
Note

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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