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Potentiation of the Selective Effect of Antibiotics by Metal Ions
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.ORCID iD: 0000-0001-6640-2174
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Complex mixtures of antibiotics and metals are present in many environments ranging from municipal sewage to irrigation water and manure used as agricultural fertilizer. Such mixtures of drugs and metals exert unique selection pressures on local bacterial communities and could function as hotspots for enrichment of antibiotic resistance genes. The presence of metals in the environment has previously been linked to increases in tolerance to antibiotics. In this study, we investigated metal-potentiated selection of antibiotic resistant Salmonella enterica strains. Six environmentally relevant metals were examined in combinations with three different antibiotics. By performing competitions between an antibiotic resistant mutant and the isogenic wild type in each metal-antibiotic combination, we assessed the minimal selective concentration (MSC) of the antibiotic for the resistant strain. The metals silver, cadmium and mercury all exhibited potentiating effects, reducing the MSC of the antibiotic up to 5-fold as compared to in the absence of the metal. We further show that the potentiating metals increased permeability of the cellular outer membrane. These results demonstrate that the presence of a metal can decrease the concentration of an antibiotic required to select for an antibiotic resistant strain, and they indicate that this process involves metal-facilitated uptake of the antibiotic following damage to the outer membrane.

Keywords [en]
Antibiotic resistance, Selection
National Category
Other Medical Sciences not elsewhere specified
Identifiers
URN: urn:nbn:se:uu:diva-356966OAI: oai:DiVA.org:uu-356966DiVA, id: diva2:1237647
Available from: 2018-08-09 Created: 2018-08-09 Last updated: 2018-08-10
In thesis
1. Antibiotic Resistance: Selection in the Presence of Metals and Antimicrobials
Open this publication in new window or tab >>Antibiotic Resistance: Selection in the Presence of Metals and Antimicrobials
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The external environment is complex: Antibiotics, metals and antimicrobials do not exist in isolation but in mixtures. Human activities such as animal husbandry, fertilization of agricultural fields and human medicine release high amounts these compounds into the environment. The work in this thesis contributes to our understanding of how the selection of bacterial antibiotic resistance can be facilitated by the pollution by metals and antimicrobials. We show that low levels of antibiotics, metals and combinations thereof can lead to the selection of chromosomally encoded antibiotic resistance genes as well as a multidrug resistance plasmid. The underlying genetic and cellular mechanisms of selection identified relate to mutational changes in a plasmid-encoded metal resistance operon, and metal-associated increases in cellular membrane permeability. We further show that exposure to quaternary ammonium compounds can result in cross-resistance to antibiotics following genetic changes in genes related to efflux, membrane synthesis and transcription/translation. Taken together, the work in this thesis suggests that the stewardship of antibiotics should include prudent use of metals and antimicrobials. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 53
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1488
Keywords
Antibiotic resistance, Metals, Antimicrobials, Bacterial evolution, Bacterial genetics
National Category
Microbiology Genetics Evolutionary Biology
Research subject
Biology with specialization in Microbiology
Identifiers
urn:nbn:se:uu:diva-356970 (URN)978-91-513-0412-0 (ISBN)
Public defence
2018-10-05, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-09-14 Created: 2018-08-10 Last updated: 2018-10-02

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Albrecht, Lisa MAndersson, Dan I
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