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Multi-Resistance Plasmids: Fitness Costs, Dynamics and Evolution
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0002-4211-5696
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 [en]
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: urn:nbn:se:uu:diva-389855ISBN: 978-91-513-0708-4 (print)OAI: oai:DiVA.org:uu-389855DiVA, id: diva2:1340814
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
List of papers
1. Dynamics of Resistance Plasmids in Extended-Spectrum-beta-Lactamase-Producing Enterobacteriaceae during Postinfection Colonization
Open this publication in new window or tab >>Dynamics of Resistance Plasmids in Extended-Spectrum-beta-Lactamase-Producing Enterobacteriaceae during Postinfection Colonization
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2019 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 63, no 4, article id e02201-18Article in journal (Refereed) Published
Abstract [en]

Extended-spectrum beta-lactamase-producing Enterobacteriaceae (EPE) are a major cause of bloodstream infections, and the colonization rate of EPE in the gut microbiota of individuals lacking prior hospitalization or comorbidities is increasing. In this study, we performed an in-depth investigation of the temporal dynamics of EPE and their plasmids during one year by collecting fecal samples from three patients initially seeking medical care for urinary tract infections. In two of the patients, the same strain that caused the urinary tract infection ( UTI) was found at all consecutive samplings from the gut microbiota, and no other EPEs were detected, while in the third patient the UTI strain was only found in the initial UTI sample. Instead, this patient presented a complex situation where a mixed microbiota of different EPE strain types, including three different E. coli ST131 variants, as well as different bacterial species, was identified over the course of the study. Different plasmid dynamics were displayed in each of the patients, including the spread of plasmids between different strain types over time and the transposition of bla(CTX-M-15) from the chromosome to a plasmid, followed by subsequent loss through homologous recombination. Small cryptic plasmids were found in all isolates from all patients, and they appear to move frequently between different strains in the microbiota. In conclusion, we could demonstrate an extensive variation of EPE strain types, plasmid composition, rearrangements, and horizontal gene transfer of genetic material illustrating the high dynamics nature and interactive environment of the gut microbiota during post-UTI carriage.

Place, publisher, year, edition, pages
AMER SOC MICROBIOLOGY, 2019
Keywords
antibiotic resistance, colonization, ESBL, Enterobacteriaceae, plasmid
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-381565 (URN)10.1128/AAC.02201-18 (DOI)000462474100047 ()30745391 (PubMedID)
Funder
Swedish Research Council, K2013-99X-22208-01-5Carl Tryggers foundation , CTS11:403Magnus Bergvall Foundation
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2019-04-16 Created: 2019-04-16 Last updated: 2019-08-06Bibliographically approved
2. The role of antibiotic resistance genes in the fitness cost of multi-resistance plasmids
Open this publication in new window or tab >>The role of antibiotic resistance genes in the fitness cost of multi-resistance plasmids
(English)Manuscript (preprint) (Other academic)
National Category
Natural Sciences Microbiology
Identifiers
urn:nbn:se:uu:diva-389853 (URN)
Available from: 2019-07-30 Created: 2019-07-30 Last updated: 2019-08-06
3. Evolutionary trajectories towards high-level β-lactam/β-lactamase inhibitor resistance of a multi-resistance plasmid carrying multiple β-lactamases
Open this publication in new window or tab >>Evolutionary trajectories towards high-level β-lactam/β-lactamase inhibitor resistance of a multi-resistance plasmid carrying multiple β-lactamases
(English)Manuscript (preprint) (Other academic)
National Category
Microbiology Evolutionary Biology
Identifiers
urn:nbn:se:uu:diva-389854 (URN)
Available from: 2019-07-30 Created: 2019-07-30 Last updated: 2019-08-06

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