Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host

  1. Brittany Rosener
  2. Serkan Sayin
  3. Peter O Oluoch
  4. Aurian P García González
  5. Hirotada Mori
  6. Albertha JM Walhout
  7. Amir Mitchell  Is a corresponding author
  1. University of Massachusetts Medical School, United States
  2. 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

The following previously published data sets were used

Article and author information

Author details

  1. Brittany Rosener

    Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Serkan Sayin

    Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Peter O Oluoch

    Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7451-4993
  4. Aurian P García González

    Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Hirotada Mori

    Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Japan
    Competing interests
    The authors declare that no competing interests exist.
  6. Albertha JM Walhout

    Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5587-3608
  7. Amir Mitchell

    Program in Systems Biology, Program in Molecular Medicine, Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    amir.mitchell@umassmed.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9376-3987

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.

Reviewing Editor

  1. Christian R Landry, Université Laval, Canada

Version history

  1. Received: June 9, 2020
  2. Accepted: November 25, 2020
  3. Accepted Manuscript published: November 30, 2020 (version 1)
  4. Version of Record published: December 9, 2020 (version 2)

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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  1. Brittany Rosener
  2. Serkan Sayin
  3. Peter O Oluoch
  4. Aurian P García González
  5. Hirotada Mori
  6. Albertha JM Walhout
  7. Amir Mitchell
(2020)
Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host
eLife 9:e59831.
https://doi.org/10.7554/eLife.59831

Share this article

https://doi.org/10.7554/eLife.59831

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