G5 Doctoral dissertation (article)
Extended-spectrum β-lactamase-producing Enterobacteriaceae : risks during antibiotic treatment and potential solutions to cure carriage (2019)
Ruotsalainen, P. (2019). Extended-spectrum β-lactamase-producing Enterobacteriaceae : risks during antibiotic treatment and potential solutions to cure carriage [Doctoral dissertation]. Jyväskylän yliopisto. JYU dissertations, 107. http://urn.fi/URN:ISBN:978-951-39-7819-8
JYU authors or editors
Publication details
All authors or editors: Ruotsalainen, Pilvi
eISBN: 978-951-39-7819-8
Journal or series: JYU dissertations
eISSN: 2489-9003
Publication year: 2019
Number in series: 107
Number of pages in the book: 1 verkkoaineisto (89 sivua, 28 sivua useina numerointijaksoina, 10 numeroimatonta sivua) :
Publisher: Jyväskylän yliopisto
Place of Publication: Jyväskylä
Publication country: Finland
Publication language: English
Persistent website address: http://urn.fi/URN:ISBN:978-951-39-7819-8
Publication open access: Openly available
Publication channel open access: Open Access channel
Abstract
global emergence of antibiotic-resistant bacteria. This is largely due to the rapid
spread of multi-resistance plasmids in bacterial communities via conjugation.
The increased carriage of extended-spectrum β-lactamase (ESBL)-producing
Enterobacteriaceae in the human gut increases the probability of conjugative ESBL
plasmids spreading to new bacterial hosts. Therefore, identifying factors that
affect the dispersal of plasmids is essential to control their spread. In this thesis,
I demonstrate that bacteria-harbouring ESBL plasmids can evolutionarily rescue
antibiotic-susceptible cells in a bacterial community via conjugation even under
lethal β-lactam concentrations. Thus, antibiotic-sensitive pathogens may also
become resistant after an apparently efficient treatment is initiated. In this thesis,
a conjugative clustered regularly interspaced short palindromic repeats
(CRISPR)-Cas9 plasmid system (i.e., midbiotics) was developed to eradicate
sequence-specifically different ESBL-bacteria from bacterial community, such as
gut microflora. Several genes can be targeted simultaneously with a single
midbiotic plasmid. The dispersal of the midbiotic plasmids results in efficient resensitisation of the exposed strains to β-lactams. However, before introducing
this system in vivo, the following concerns need to be resolved: the dissemination
of unwanted genes in the flora, mutations that nullify CRISPR activity, and the
spread of the conjugative plasmid without its ESBL-targeting plasmid partner. In
addition to midbiotics, lytic phages, which infect and kill resistant bacterial
pathogens, may provide a potential option to decrease ESBL carriage. In this
thesis, it was demonstrated that phages can be isolated on-demand from
environmental reservoirs to carry out personalised phage therapy against
Enterobacteriaceae, which are frequently associated with ESBL infections.
Keywords: Enterobacteriaceae; antibiotic resistance; horizontal gene transfer; plasmids; bacteriophages; phage therapy; gene technology
Free keywords: antibiotic resistance; horizontal gene transfer; conjugative plasmids; bacteriophages; phage therapy; CRISPR-Cas9
Contributing organizations
Ministry reporting: Yes
Reporting Year: 2019
