UMMS Affiliation

Program in Systems Biology; Program in Molecular Medicine; Department of Molecular, Cell and Cancer Biology; Graduate School of Biomedical Sciences

Publication Date

2020-11-30

Document Type

Article

Disciplines

Bacteria | Computational Biology | Molecular Biology | Systems and Integrative Physiology | Systems Biology

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 Caenorhabditis 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.

Keywords

C. elegans, E. coli, chemotherapy, computational biology, drug adaptation, drug resistance, evolutionary adaptation, microbiome, systems biology

Rights and Permissions

Copyright Rosener et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

DOI of Published Version

10.7554/eLife.59831

Source

Rosener B, Sayin S, Oluoch PO, García González AP, Mori H, Walhout AJ, Mitchell A. Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host. Elife. 2020 Nov 30;9:e59831. doi: 10.7554/eLife.59831. PMID: 33252330; PMCID: PMC7725501. Link to article on publisher's site

Journal/Book/Conference Title

eLife

Related Resources

Link to Article in PubMed

PubMed ID

33252330

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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