Bacterial persistence promotes the evolution of antibiotic resistance by increasing survival and mutation rates

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Abstract

Persisters are transiently antibiotic-tolerant cells that complicate the treatment of bacterial infections. Both theory and experiments have suggested that persisters facilitate genetic resistance by constituting an evolutionary reservoir of viable cells. Here, we provide evidence for a strong positive correlation between persistence and the likelihood to become genetically resistant in natural and lab strains of E. coli. This correlation can be partly attributed to the increased availability of viable cells associated with persistence. However, our data additionally show that persistence is pleiotropically linked with mutation rates. Our theoretical model further demonstrates that increased survival and mutation rates jointly affect the likelihood of evolving clinical resistance. Overall, these results suggest that the battle against antibiotic resistance will benefit from incorporating anti-persister therapies.

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Acknowledgements

We thank Chris Michiels (KU Leuven) for providing ECOR strains, Abram Aertsen (KU Leuven) for sharing the hipA7 strain, and Bernard Ycart and Adrien Mazoyer (Grenoble Alpes University) for their assistance with fluctuation analysis. EMW and BVdB are Research Foundation—Flanders (FWO)-fellows and JEM is a fellow of the Agency for Innovation by Science and Technology (IWT). This research was funded by the KU Leuven Research Council (PF/10/010; C16/17/006), the Belgian Science Policy Office (IAP P7/28), FWO (G047112N; G0B2515N; G055517N), and the Flemish Institute for Biotechnology (VIB).

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Correspondence to Jan Michiels.

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Windels, E.M., Michiels, J.E., Fauvart, M. et al. Bacterial persistence promotes the evolution of antibiotic resistance by increasing survival and mutation rates. ISME J 13, 1239–1251 (2019) doi:10.1038/s41396-019-0344-9

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