1. Computational and Systems Biology

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

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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Further reading

    1. Computational and Systems Biology
    2. Evolutionary Biology

    Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy in co-cultured cancer cells

    Serkan Sayin, Brittany Rosener ... Amir Mitchell
    Research Advance Updated

    Drug metabolism by the microbiome can influence anticancer treatment success. We previously suggested that chemotherapies with antimicrobial activity can select for adaptations in bacterial drug metabolism that can inadvertently influence the host’s chemoresistance. We demonstrated that evolved resistance against fluoropyrimidine chemotherapy lowered its efficacy in worms feeding on drug-evolved bacteria (Rosener et al., 2020). Here, we examine a model system that captures local interactions that can occur in the tumor microenvironment. Gammaproteobacteria-colonizing pancreatic tumors can degrade the nucleoside-analog chemotherapy gemcitabine and, in doing so, can increase the tumor’s chemoresistance. Using a genetic screen in Escherichia coli, we mapped all loss-of-function mutations conferring gemcitabine resistance. Surprisingly, we infer that one third of top resistance mutations increase or decrease bacterial drug breakdown and therefore can either lower or raise the gemcitabine load in the local environment. Experiments in three E. coli strains revealed that evolved adaptation converged to inactivation of the nucleoside permease NupC, an adaptation that increased the drug burden on co-cultured cancer cells. The two studies provide complementary insights on the potential impact of microbiome adaptation to chemotherapy by showing that bacteria–drug interactions can have local and systemic influence on drug activity.