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The role of antibiotic resistance genes in the fitness cost of multi-resistance plasmids
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Linus Sandegren)ORCID iD: 0000-0002-4211-5696
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
(English)Manuscript (preprint) (Other academic)
National Category
Natural Sciences Microbiology
Identifiers
URN: urn:nbn:se:uu:diva-389853OAI: oai:DiVA.org:uu-389853DiVA, id: diva2:1339543
Available from: 2019-07-30 Created: 2019-07-30 Last updated: 2019-08-06
In thesis
1. Multi-Resistance Plasmids: Fitness Costs, Dynamics and Evolution
Open this publication in new window or tab >>Multi-Resistance Plasmids: Fitness Costs, Dynamics and Evolution
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibiotic resistance is an escalating problem, not only due to less desirable treatment options and outcome, but also due to the economic burden to health care caused by resistant pathogens. Since the process of developing new antibiotics is slow, we need to carefully consider the usage of the antibiotics still available. Therefore it is of importance to minimize the development and spread of resistant pathogens. To do so, we need a better understanding of the mechanisms and dynamics underlying the evolution of highly resistant bacteria.

In this thesis I have investigated one of the major drivers of resistance gene dissemination in Gram-negative bacteria, namely multi-resistance plasmids. We show that multi-resistance plasmids display a dynamic behavior in vivo, where genes can be readily acquired and lost again. Additionally, plasmids can be shared amongst different bacteria, especially in environments such as the human gut. Interestingly, some resistance plasmids confer a fitness disadvantage to their host displayed by decreased growth rate in absence of antibiotics. We could elucidate that two resistance genes of the multi-resistance plasmid pUUH239.2 were the cause of the lowered growth rate, namely blaCTX-M-15 and tetR/A. In contrast, other resistance genes on the plasmid were cost-free even when overexpressed and likely enable persistence in the bacterial population even under non-selective conditions. Lastly, we studied how the presence of several β-lactamase genes on a plasmid affects treatment with different combinations of β-lactam/β-lactamase inhibitors. We found that an efficient mechanism for bacteria to overcome high levels of antibiotics was by amplification of plasmid-borne resistance genes. This mechanism works as a stepping-stone for additional mutations giving rise to high-level resistance.

With this work we provide insight into the mechanisms underlying resistance evolution and dissemination due to multi-resistance plasmids. Plasmids enable fast dissemination of multiple resistance genes and therefore simultaneously disable multiple treatment options. Examining the effects of resistance genes and antibiotics on strains carrying multi-resistance plasmids will enable us to understand what factors assist or inhibit plasmid spread. Hopefully, this will aid us in treatment design to prevent resistance development to effective antibiotics and have implications for resistance surveillance as well as prediction.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 85
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1587
Keywords
multi-resistance plasmids, evolution, fitness cost, dynamics, escherichia coli, ESBL, gene amplification, β-lactamase inhibitor
National Category
Microbiology Evolutionary Biology
Research subject
Biology with specialization in Microbiology
Identifiers
urn:nbn:se:uu:diva-389855 (URN)978-91-513-0708-4 (ISBN)
Public defence
2019-09-27, Room B:42, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2019-09-05 Created: 2019-08-06 Last updated: 2019-09-17

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CiteExportLink to record
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