Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host
- University of Massachusetts Medical School, United States
- Nara Institute of Science and Technology, Japan
Abstract
Metabolism of host-targeted drugs by the microbiome can substantially impact host treatment success. However, since many host-targeted drugs inadvertently hamper microbiome growth, repeated drug administration can lead to microbiome evolutionary adaptation. We tested if evolved bacterial resistance against host-targeted drugs alters their drug metabolism and impacts host treatment success. We used a model system of C. elegans, its bacterial diet, and two fluoropyrimidine chemotherapies. Genetic screens revealed that most of loss-of-function resistance mutations in Escherichia coli also reduced drug toxicity in the host. We found that resistance rapidly emerged in E. coli under natural selection and converged to a handful of resistance mechanisms. Surprisingly, we discovered that nutrient availability during bacterial evolution dictated the dietary effect on the host – only bacteria evolving in nutrient-poor media reduced host drug toxicity. Our work suggests that bacteria can rapidly adapt to host-targeted drugs and by doing so may also impact the host.
Data availability
Sequencing data was deposited in SRA under the BioProjects IDs PRJNA645604 and PRJNA645605
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Table S2Supplementary information, mmc2.xlsx.
Article and author information
Author details
Albertha JM Walhout
Funding
NIGMS (R35GM133775)
- Amir Mitchell
NIGMS (DK068429)
- Albertha JM Walhout
NIGMS (GM122393)
- Aurian P García González
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Rosener et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host
eLife 9:e59831.
https://doi.org/10.7554/eLife.59831
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