Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host
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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/59831 |
| _version_ | 1818019332923326464 |
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| author | Brittany Rosener Serkan Sayin Peter O Oluoch Aurian P García González Hirotada Mori Albertha JM Walhout Amir Mitchell |
| author_facet | Brittany Rosener Serkan Sayin Peter O Oluoch Aurian P García González Hirotada Mori Albertha JM Walhout Amir Mitchell |
| author_sort | Brittany Rosener |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T07:50:54Z |
| format | Article |
| id | doaj.art-7f1eba23afaf4b36ad54274bc601c6ea |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:50:54Z |
| publishDate | 2020-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7f1eba23afaf4b36ad54274bc601c6ea2022-12-22T02:05:12ZengeLife Sciences Publications LtdeLife2050-084X2020-11-01910.7554/eLife.59831Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans hostBrittany Rosener0https://orcid.org/0000-0002-1836-8503Serkan Sayin1https://orcid.org/0000-0001-8776-2240Peter O Oluoch2https://orcid.org/0000-0001-7451-4993Aurian P García González3Hirotada Mori4https://orcid.org/0000-0003-3855-778XAlbertha JM Walhout5https://orcid.org/0000-0001-5587-3608Amir Mitchell6https://orcid.org/0000-0001-9376-3987Program in Systems Biology, University of Massachusetts Medical School, Worcester, United StatesProgram in Systems Biology, University of Massachusetts Medical School, Worcester, United StatesProgram in Systems Biology, University of Massachusetts Medical School, Worcester, United StatesProgram in Systems Biology, University of Massachusetts Medical School, Worcester, United StatesData Science Center, Nara Institute of Science and Technology, Ikoma, JapanProgram in Systems Biology, University of Massachusetts Medical School, Worcester, United States; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United StatesProgram in Systems Biology, University of Massachusetts Medical School, Worcester, United States; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, United StatesMetabolism 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.https://elifesciences.org/articles/59831evolutionary adaptationchemotherapymicrobiomedrug resistancedrug adaptation |
| spellingShingle | Brittany Rosener Serkan Sayin Peter O Oluoch Aurian P García González Hirotada Mori Albertha JM Walhout Amir Mitchell Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host eLife evolutionary adaptation chemotherapy microbiome drug resistance drug adaptation |
| title | Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host |
| title_full | Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host |
| title_fullStr | Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host |
| title_full_unstemmed | Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host |
| title_short | Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host |
| title_sort | evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the caenorhabditis elegans host |
| topic | evolutionary adaptation chemotherapy microbiome drug resistance drug adaptation |
| url | https://elifesciences.org/articles/59831 |
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