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Predictable Phenotypes of Antibiotic Resistance Mutations
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0002-8218-3263
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0001-6640-2174
2018 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 9, no 3, article id e00770-18Article in journal (Refereed) Published
Abstract [en]

The spread of antibiotic-resistant bacteria imposes an urgent threat to public health. The ability to forecast the evolutionary success of resistant mutants would help to combat dissemination of antibiotic resistance. Previous studies have shown that the phenotypic effects (fitness and resistance level) of resistance mutations can vary substantially depending on the genetic context in which they occur. We conducted a broad screen using many different resistance mutations and host strains to identify potential epistatic interactions between various types of resistance mutations and to determine the effect of strain background on resistance phenotypes. Combinations of several different mutations showed a large amount of phenotypic predictability, and the majority of the mutations displayed strain-independent phenotypes. However, we also identified a few outliers from these patterns, illustrating that the choice of host organism can be critically important when studying antibiotic resistance mutations.

Place, publisher, year, edition, pages
2018. Vol. 9, no 3, article id e00770-18
Keywords [en]
Escherichia coli, Salmonella, Strain specificity, antibiotic resistance, epistasis, fitness
National Category
Microbiology
Identifiers
URN: urn:nbn:se:uu:diva-353492DOI: 10.1128/mBio.00770-18ISI: 000433051200042PubMedID: 29764951OAI: oai:DiVA.org:uu-353492DiVA, id: diva2:1217546
Funder
Swedish Research CouncilSwedish Research Council FormasAvailable from: 2018-06-13 Created: 2018-06-13 Last updated: 2018-08-13Bibliographically approved
In thesis
1. Mechanisms of Antibiotic Resistance Evolution
Open this publication in new window or tab >>Mechanisms of Antibiotic Resistance Evolution
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The continuing emergence and spread of antibiotic resistant bacteria are a threat to various applications in modern medicine and impose a strong economic burden on health systems. The development of new antibiotics is slow and cannot counterbalance the dissemination of resistant bacteria. Thus, we need to find ways to reduce the rate of antibiotic resistance development. For this, we need to acquire a deeper understanding of the mechanisms underlying the evolution of antibiotic resistance.

Here, we investigate the factors that govern how antibiotic resistance mechanisms affect bacterial fitness and the overall level of resistance. Using porin-deficient mutants of Escherichia coli, we show that upregulation of alternative porins provides compensatory mechanisms that can ameliorate the fitness costs associated with resistance. Furthermore, we demonstrate that the phenotypic effects of antibiotic resistance mutations are largely predictable, both in combination with each other as well as in different bacterial strains. However, outliers from this trend exemplify the limitations of solely relying on laboratory strains for the characterization of antibiotic resistance mechanisms. In contrast, strong epistatic interactions were observed in mutants evolved at sub-lethal concentrations of streptomycin. Despite these low concentrations and weak selective pressure, strains of Salmonella Typhimurium evolved high-level resistance, which followed completely different mutational pathways compared to high-level selection. Finally, we show that aminoglycoside resistance genes can be selected de novo from the expression of completely randomized nucleotide sequences. This demonstrates that new genes can arise from pools of non-coding sequences and that this process is relatively common.

The studies presented in this thesis provide insights into the mechanistic basis of resistance evolution, including the mutational spectrum causing antibiotic resistance, compensatory pathways for growth-restoration and the influence of epistatic interactions on the phenotypic expression of resistance mutations. Understanding these factors in detail will enable us to better predict and prevent the emergence of antibiotic resistance development, through improvements in surveillance, treatment regimens and drug development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 59
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1477
Keywords
Antibiotic resistance evolution, Escherichia coli, Salmonella, porins, fitness, epistasis, strain-specificity, sub-MIC, de novo gene evolution
National Category
Microbiology Evolutionary Biology
Identifiers
urn:nbn:se:uu:diva-355532 (URN)978-91-513-0384-0 (ISBN)
Public defence
2018-09-15, B41, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2018-08-16 Created: 2018-06-30 Last updated: 2018-08-27

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Knopp, MichaelAndersson, Dan I

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