Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies
<jats:title>Abstract</jats:title><jats:p>Antibiotic tolerance, or the ability of bacteria to survive antibiotic treatment in the absence of genetic resistance, has been linked to chronic and recurrent infections. Tolerant cells are often characterized by a low metabolic state, agai...
| Main Authors: | , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2023
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| Online Access: | https://hdl.handle.net/1721.1/147786 |
| _version_ | 1826194302194155520 |
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| author | Zheng, Erica J Andrews, Ian W Grote, Alexandra T Manson, Abigail L Alcantar, Miguel A Earl, Ashlee M Collins, James J |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Zheng, Erica J Andrews, Ian W Grote, Alexandra T Manson, Abigail L Alcantar, Miguel A Earl, Ashlee M Collins, James J |
| author_sort | Zheng, Erica J |
| collection | MIT |
| description | <jats:title>Abstract</jats:title><jats:p>Antibiotic tolerance, or the ability of bacteria to survive antibiotic treatment in the absence of genetic resistance, has been linked to chronic and recurrent infections. Tolerant cells are often characterized by a low metabolic state, against which most clinically used antibiotics are ineffective. Here, we show that tolerance readily evolves against antibiotics that are strongly dependent on bacterial metabolism, but does not arise against antibiotics whose efficacy is only minimally affected by metabolic state. We identify a mechanism of tolerance evolution in <jats:italic>E. coli</jats:italic> involving deletion of the sodium-proton antiporter gene <jats:italic>nhaA</jats:italic>, which results in downregulated metabolism and upregulated stress responses. Additionally, we find that cycling of antibiotics with different metabolic dependencies interrupts evolution of tolerance in vitro, increasing the lifetime of treatment efficacy. Our work highlights the potential for limiting the occurrence and extent of tolerance by accounting for antibiotic dependencies on bacterial metabolism.</jats:p> |
| first_indexed | 2024-09-23T09:53:57Z |
| format | Article |
| id | mit-1721.1/147786 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:53:57Z |
| publishDate | 2023 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1477862023-02-01T03:46:19Z Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies Zheng, Erica J Andrews, Ian W Grote, Alexandra T Manson, Abigail L Alcantar, Miguel A Earl, Ashlee M Collins, James J Massachusetts Institute of Technology. Department of Biological Engineering <jats:title>Abstract</jats:title><jats:p>Antibiotic tolerance, or the ability of bacteria to survive antibiotic treatment in the absence of genetic resistance, has been linked to chronic and recurrent infections. Tolerant cells are often characterized by a low metabolic state, against which most clinically used antibiotics are ineffective. Here, we show that tolerance readily evolves against antibiotics that are strongly dependent on bacterial metabolism, but does not arise against antibiotics whose efficacy is only minimally affected by metabolic state. We identify a mechanism of tolerance evolution in <jats:italic>E. coli</jats:italic> involving deletion of the sodium-proton antiporter gene <jats:italic>nhaA</jats:italic>, which results in downregulated metabolism and upregulated stress responses. Additionally, we find that cycling of antibiotics with different metabolic dependencies interrupts evolution of tolerance in vitro, increasing the lifetime of treatment efficacy. Our work highlights the potential for limiting the occurrence and extent of tolerance by accounting for antibiotic dependencies on bacterial metabolism.</jats:p> 2023-01-30T18:49:26Z 2023-01-30T18:49:26Z 2022-05-09 2023-01-30T18:30:06Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/147786 Zheng, Erica J, Andrews, Ian W, Grote, Alexandra T, Manson, Abigail L, Alcantar, Miguel A et al. 2022. "Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies." Nature Communications, 13 (1). en 10.1038/s41467-022-30272-0 Nature Communications Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | Zheng, Erica J Andrews, Ian W Grote, Alexandra T Manson, Abigail L Alcantar, Miguel A Earl, Ashlee M Collins, James J Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies |
| title | Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies |
| title_full | Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies |
| title_fullStr | Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies |
| title_full_unstemmed | Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies |
| title_short | Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies |
| title_sort | modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies |
| url | https://hdl.handle.net/1721.1/147786 |
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