Extended-spectrum β-lactamase-producing Enterobacteriaceae: risks during antibiotic treatment and potential solutions to cure carriage
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: Antibiotic resistance; horizontal gene transfer; conjugative plasmids;
bacteriophages; phage therapy; CRISPR-Cas9.
...
Publisher
Jyväskylän yliopistoISBN
978-951-39-7819-8ISSN Search the Publication Forum
2489-9003Contains publications
- Artikkeli I: Mattila, S., Ruotsalainen, P., Ojala, V., Tuononen, T., Hiltunen, T., & Jalasvuori, M. (2017). Conjugative ESBL plasmids differ in their potential to rescue susceptible bacteria via horizontal gene transfer in lethal antibiotic concentrations. Journal of Antibiotics, 70, 805-808. DOI: 10.1038/ja.2017.41
- Artikkeli II: Ruotsalainen P., Penttinen R. & Jalasvuori M. (2019). Evolutionary rescue by ESBLplasmid-conjugation in lethal penam and cephem concentrations. Manuscript.
- Artikkeli III: Ruotsalainen, P., Penttinen, R., Mattila, S., & Jalasvuori, M. (2019). Midbiotics : conjugative plasmids for genetic engineering of natural gut flora. Gut Microbes, 10 (6), 643-653. DOI: 10.1080/19490976.2019.1591136
- Artikkeli IV: Mattila, S., Ruotsalainen, P., & Jalasvuori, M. (2015). On-Demand Isolation of Bacteriophages Against Drug-Resistant Bacteria for Personalized Phage Therapy. Frontiers in Microbiology, 6, 1271. DOI: 10.3389/fmicb.2015.01271
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