G5 Doctoral dissertation (article)
Extended-spectrum β-lactamase-producing Enterobacteriaceae : risks during antibiotic treatment and potential solutions to cure carriage (2019)


Ruotsalainen, Pilvi (2019). Extended-spectrum β-lactamase-producing Enterobacteriaceae : risks during antibiotic treatment and potential solutions to cure carriage. JYU dissertations, 107. Jyväskylä: Jyväskylän yliopisto. 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

Open Access: Publication published in an open access channel


Abstract

The abundant consumption and negligent use of antibiotics have resulted in the
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


Last updated on 2020-09-07 at 11:47