Identifying and exploiting genes that potentiate the evolution of antibiotic resistance

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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Fig. 1: Responses of Pseudomonas to ceftazidime.
Fig. 2: Resistance in evolved clones.
Fig. 3: The AmpR transcription factor potentiates the evolution of ceftazidime resistance in P. aeruginosa PAO1.
Fig. 4: Blocking the evolution of ceftazidime 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).

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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.

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

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Gifford, D.R., Furió, V., Papkou, A. et al. Identifying and exploiting genes that potentiate the evolution of antibiotic resistance. Nat Ecol Evol 2, 1033–1039 (2018). https://doi.org/10.1038/s41559-018-0547-x

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