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Nat Ecol Evol. 2016 Nov 7;1(1):10. doi: 10.1038/s41559-016-0010.

Multicopy plasmids potentiate the evolution of antibiotic resistance in bacteria.

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Department of Zoology, University of Oxford, Oxford OX1 3PS, UK.
Department of Microbiology, Hospital Universitario Ramon y Cajal (IRYCIS), 28034 Madrid, Spain.
Institut Pasteur, Unité de Plasticité du Génome Bactérien, Département Génomes et Génétique, 28 Rue du Dr. Roux, 75015 Paris, France.
CNRS, UMR3525, 28 Rue du Dr. Roux, 75015 Paris, France.


Plasmids are thought to play a key role in bacterial evolution by acting as vehicles for horizontal gene transfer, but the role of plasmids as catalysts of gene evolution remains unexplored. We challenged populations of Escherichia coli carrying the blaTEM-1 β-lactamase gene on either the chromosome or a multicopy plasmid (19 copies per cell) with increasing concentrations of ceftazidime. The plasmid accelerated resistance evolution by increasing the rate of appearance of novel TEM-1 mutations, thereby conferring resistance to ceftazidime, and then by amplifying the effect of TEM-1 mutations due to the increased gene dosage. Crucially, this dual effect was necessary and sufficient for the evolution of clinically relevant levels of resistance. Subsequent evolution occurred by mutations in a regulatory RNA that increased the plasmid copy number, resulting in marginal gains in ceftazidime resistance. These results uncover a role for multicopy plasmids as catalysts for the evolution of antibiotic resistance in bacteria.


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