Bacteria gain antibiotic resistance genes by horizontal acquisition of mobile genetic elements (MGEs) from other lineages. Newly acquired MGEs are often poorly adapted causing intragenomic conflicts; these are resolved by either compensatory adaptation—of the chromosome or the MGE—or reciprocal coadaptation. The footprints of such intragenomic coevolution are present in bacterial genomes, suggesting an important role promoting genomic integration of horizontally acquired genes, but direct experimental evidence of the process is limited. Here we show adaptive modulation of tetracycline resistance via intragenomic coevolution between Escherichia coli and the multidrug resistant plasmid RK2. Tetracycline treatments, including monotherapy or combination therapies with ampicillin, favoured de novo chromosomal resistance mutations coupled with mutations on RK2 impairing the plasmid-encoded tetracycline efflux pump. These mutations together provided increased tetracycline resistance at reduced cost. Additionally, the chromosomal resistance mutations conferred cross-resistance to chloramphenicol. Reciprocal coadaptation was not observed under ampicillin-only or no antibiotic selection. Intragenomic coevolution can create genomes comprising multiple replicons that together provide high-level, low-cost resistance, but the resulting co-dependence may limit the spread of coadapted MGEs to other lineages.
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We thank J. P. W. Young, V. Friman, and members of the Friman and Brockhurst laboratories for discussion and comments on the manuscript. We thank C. M. Thomas for providing pCURE plasmids. This research was supported by the Wellcome Trust four-year PhD programme (WT095024MA) ‘Combating infectious disease: computational approaches in translation science’. This work was also supported by funding from the European Research Council under the European Union’s Seventh Framework Programme awarded to M.A.B. (FP7/2007-2013 ERC grant StG-2012-311490–COEVOCON).
The authors declare no competing financial interests.
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Bottery, M.J., Wood, A.J. & Brockhurst, M.A. Adaptive modulation of antibiotic resistance through intragenomic coevolution. Nat Ecol Evol 1, 1364–1369 (2017). https://doi.org/10.1038/s41559-017-0242-3
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