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Evolution of high-level resistance during low-level antibiotic exposure
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0002-2753-1480
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.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.ORCID iD: 0000-0002-3275-0936
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, no 1, article id 1599Article in journal (Refereed) Published
Abstract [en]

It has become increasingly clear that low levels of antibiotics present in many environments can select for resistant bacteria, yet the evolutionary pathways for resistance development during exposure to low amounts of antibiotics remain poorly defined. Here we show that Salmonella enterica exposed to sub-MIC levels of streptomycin evolved high-level resistance via novel mechanisms that are different from those observed during lethal selections. During lethal selection only rpsL mutations are found, whereas at sub-MIC selection resistance is generated by several small-effect resistance mutations that combined confer high-level resistance via three different mechanisms: (i) alteration of the ribosomal RNA target (gidB mutations), (ii) reduction in aminoglycoside uptake (cyoB, nuoG, and trkH mutations), and (iii) induction of the aminoglycoside-modifying enzyme AadA (znuA mutations). These results demonstrate how the strength of the selective pressure influences evolutionary trajectories and that even weak selective pressures can cause evolution of high-level resistance.

Place, publisher, year, edition, pages
2018. Vol. 9, no 1, article id 1599
National Category
Microbiology
Identifiers
URN: urn:nbn:se:uu:diva-353487DOI: 10.1038/s41467-018-04059-1ISI: 000430541900015PubMedID: 29686259OAI: oai:DiVA.org:uu-353487DiVA, id: diva2:1217545
Funder
Swedish Research CouncilSwedish Research Council FormasAvailable from: 2018-06-13 Created: 2018-06-13 Last updated: 2018-06-30Bibliographically 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)
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Available from: 2018-08-16 Created: 2018-06-30 Last updated: 2018-08-27

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