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Identifying and exploiting genes that potentiate the evolution of antibiotic resistance

Nature Ecology & Evolutionvolume 2pages10331039 (2018) | Download Citation

Abstract

There is an urgent need to develop novel approaches for predicting and preventing the evolution of antibiotic resistance. Here, we show that the ability to evolve de novo resistance to a clinically important β-lactam antibiotic, ceftazidime, varies drastically across the genus Pseudomonas. This variation arises because strains possessing the ampR global transcriptional regulator evolve resistance at a high rate. This does not arise because of mutations in ampR. Instead, this regulator potentiates evolution by allowing mutations in conserved peptidoglycan biosynthesis genes to induce high levels of β-lactamase expression. Crucially, blocking this evolutionary pathway by co-administering ceftazidime with the β-lactamase inhibitor avibactam can be used to eliminate pathogenic P. aeruginosa populations before they can evolve resistance. In summary, our study shows that identifying potentiator genes that act as evolutionary catalysts can be used to both predict and prevent the evolution of antibiotic resistance.

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Acknowledgements

This work was supported by funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant (StG-2011-281591) and by a Wellcome Trust Senior Research Fellowship (WT106918AIA) held by R.C.M. V.F. was supported by an MEC Postdoctoral Fellowship from the Spanish government (EX-2010-0958).

Author information

Author notes

  1. These authors contributed equally: Danna R. Gifford and Victoria Furió.

Affiliations

  1. Department of Zoology, University of Oxford, Oxford, UK

    • Danna R. Gifford
    • , Victoria Furió
    • , Andrei Papkou
    • , Tom Vogwill
    •  & R. Craig MacLean
  2. Servicio de Microbiología and Unidad de Investigación, Hospital Universitario Son Espases Instituto de Investigación Sanitaria de Palma, Palma de Mallorca, Spain

    • Antonio Oliver

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Contributions

R.C.M. designed the study. V.F., A.P. and T.V. conducted the experiments. D.R.G. performed the bioinformatics analyses. V.F., A.P., D.R.G. and R.C.M. analysed the data. A.O. contributed reagents and expertise. R.C.M., D.R.G. and V.F. wrote the paper.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Danna R. Gifford or R. Craig MacLean.

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DOI

https://doi.org/10.1038/s41559-018-0547-x