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Selection of Resistant Bacteria at Very Low Antibiotic Concentrations
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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, Molecular Evolution.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2011 (English)In: PLoS pathogens, ISSN 1553-7366, Vol. 7, no 7, e1002158- p.Article in journal (Refereed) Published
Abstract [en]

The widespread use of antibiotics is selecting for a variety of resistance mechanisms that seriously challenge our ability to treat bacterial infections. Resistant bacteria can be selected at the high concentrations of antibiotics used therapeutically, but what role the much lower antibiotic concentrations present in many environments plays in selection remains largely unclear. Here we show using highly sensitive competition experiments that selection of resistant bacteria occurs at extremely low antibiotic concentrations. Thus, for three clinically important antibiotics, drug concentrations up to several hundred-fold below the minimal inhibitory concentration of susceptible bacteria could enrich for resistant bacteria, even when present at a very low initial fraction. We also show that de novo mutants can be selected at sub-MIC concentrations of antibiotics, and we provide a mathematical model predicting how rapidly such mutants would take over in a susceptible population. These results add another dimension to the evolution of resistance and suggest that the low antibiotic concentrations found in many natural environments are important for enrichment and maintenance of resistance in bacterial populations.

Place, publisher, year, edition, pages
2011. Vol. 7, no 7, e1002158- p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-157045DOI: 10.1371/journal.ppat.1002158ISI: 000293339300042OAI: oai:DiVA.org:uu-157045DiVA: diva2:434407
Available from: 2011-08-15 Created: 2011-08-15 Last updated: 2015-02-03Bibliographically approved
In thesis
1. Selection of Resistance at very low Antibiotic Concentrations
Open this publication in new window or tab >>Selection of Resistance at very low Antibiotic Concentrations
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The extensive medical and agricultural use and misuse of antibiotics during the last 70 years has caused an enrichment of resistant pathogenic bacteria that now severely threatens our capacity to efficiently treat bacterial infections. While is has been known for a long time that high concentrations of antibiotics can select for resistant mutants, less is known about the lower limit at which antibiotics can be selective and enrich for resistant bacteria.

In this thesis we investigated the role of low concentrations of antibiotics and heavy metals in the enrichment and evolution of antibiotic resistance. Selection was studied using Escherichia coli and Salmonella enterica serovar Typhimurium LT2 with different resistance mutations, different chromosomal resistance genes as well as large conjugative multidrug resistance plasmids. Using very sensitive competition experiments, we showed that antibiotic and heavy metal levels more than several hundred-fold below the minimal inhibitory concentration of susceptible bacteria can enrich for resistant bacteria. Additionally, we demonstrated that subinhibitory levels of antibiotics can select for de novo resistant mutants, and that these conditions can select for a new spectrum of low-cost resistance mutations. The combinatorial effects of antibiotics and heavy metals can cause an enrichment of a multidrug resistance plasmid, even if the concentration of each compound individually is not high enough to cause selection.

These results indicate that environments contaminated with low levels of antibiotics and heavy metals such as, for example, sewage water or soil fertilized with sludge or manure, could provide a setting for selection, enrichment and transfer of antibiotic resistance genes. This selection could be a critical step in the transfer of resistance genes from environmental bacteria to human pathogens.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 86 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1053
Keyword
Antibiotic resistance, Selection, Antibiotic resistant bacteria, Minimal inhibitory concentration, Heavy metals, Conjugative plasmid, ESBL
National Category
Microbiology in the medical area
Research subject
Microbiology; Biology with specialization in Microbiology; Biology with specialization in Molecular Evolution
Identifiers
urn:nbn:se:uu:diva-235225 (URN)978-91-554-9101-7 (ISBN)
Public defence
2014-12-17, A1:111a, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2014-11-24 Created: 2014-10-29 Last updated: 2015-02-03

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