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11 30, 2020;9

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

Brittany Rosener, Serkan Sayin, Peter O Oluoch, Aurian P Garc��a Gonz��lez, Hirotada Mori, Albertha Jm Walhout, Amir Mitchell
Author Information
  1. Brittany Rosener: Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States. ORCID
  2. Serkan Sayin: Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States. ORCID
  3. Peter O Oluoch: Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States. ORCID
  4. Aurian P Garc��a Gonz��lez: Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States.
  5. Hirotada Mori: Data Science Center, Nara Institute of Science and Technology, Ikoma, Japan. ORCID
  6. Albertha Jm Walhout: Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States. ORCID
  7. Amir Mitchell: Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States. ORCID
PMID: 33252330 DOI: 10.7554/eLife.59831

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 , its bacterial diet, and two fluoropyrimidine chemotherapies. Genetic screens revealed that most of loss-of-function resistance mutations in also reduced drug toxicity in the host. We found that resistance rapidly emerged in 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

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Grants

  1. DK068429/NIGMS NIH HHS
  2. GM133775/NIGMS NIH HHS
  3. R01 DK068429/NIDDK NIH HHS
  4. F31 GM122393/NIGMS NIH HHS
  5. R56 DK068429/NIDDK NIH HHS
  6. GM122393/NIGMS NIH HHS
  7. R35 GM133775/NIGMS NIH HHS

MeSH Term

Animals
Anti-Bacterial Agents
Antimetabolites
Antimetabolites, Antineoplastic
Caenorhabditis elegans
DNA Barcoding, Taxonomic
Directed Molecular Evolution
Drug Resistance, Bacterial
Escherichia coli
Floxuridine
Fluorouracil
Gene Deletion
Pyrimidines
Sequence Analysis, RNA
Whole Genome Sequencing

Chemicals

Anti-Bacterial Agents
Antimetabolites
Antimetabolites, Antineoplastic
Pyrimidines
Floxuridine
Fluorouracil
Journal Article Research Support, N.I.H., Extramural
Article has an altmetric score of 190

Word Cloud

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