Clinically relevant mutations in core metabolic genes confer antibiotic resistance
© 2021 American Association for the Advancement of Science. All rights reserved. Although metabolism plays an active role in antibiotic lethality, antibiotic resistance is generally associated with drug target modification, enzymatic inactivation, and/or transport rather than metabolic processes. Ev...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Association for the Advancement of Science (AAAS)
2021
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| Online Access: | https://hdl.handle.net/1721.1/133494 |
| _version_ | 1826214345029189632 |
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| author | Lopatkin, Allison J Bening, Sarah C Manson, Abigail L Stokes, Jonathan M Kohanski, Michael A Badran, Ahmed H Earl, Ashlee M Cheney, Nicole J Yang, Jason H Collins, James J |
| author_facet | Lopatkin, Allison J Bening, Sarah C Manson, Abigail L Stokes, Jonathan M Kohanski, Michael A Badran, Ahmed H Earl, Ashlee M Cheney, Nicole J Yang, Jason H Collins, James J |
| author_sort | Lopatkin, Allison J |
| collection | MIT |
| description | © 2021 American Association for the Advancement of Science. All rights reserved. Although metabolism plays an active role in antibiotic lethality, antibiotic resistance is generally associated with drug target modification, enzymatic inactivation, and/or transport rather than metabolic processes. Evolution experiments of Escherichia coli rely on growth-dependent selection, which may provide a limited view of the antibiotic resistance landscape. We sequenced and analyzed E. coli adapted to representative antibiotics at increasingly heightened metabolic states. This revealed various underappreciated noncanonical genes, such as those related to central carbon and energy metabolism, which are implicated in antibiotic resistance. These metabolic alterations lead to lower basal respiration, which prevents antibiotic-mediated induction of tricarboxylic acid cycle activity, thus avoiding metabolic toxicity and minimizing drug lethality. Several of the identified metabolism-specific mutations are overrepresented in the genomes of >3500 clinical E. coli pathogens, indicating clinical relevance. |
| first_indexed | 2024-09-23T16:03:54Z |
| format | Article |
| id | mit-1721.1/133494 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T16:03:54Z |
| publishDate | 2021 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1334942021-10-28T03:13:55Z Clinically relevant mutations in core metabolic genes confer antibiotic resistance Lopatkin, Allison J Bening, Sarah C Manson, Abigail L Stokes, Jonathan M Kohanski, Michael A Badran, Ahmed H Earl, Ashlee M Cheney, Nicole J Yang, Jason H Collins, James J © 2021 American Association for the Advancement of Science. All rights reserved. Although metabolism plays an active role in antibiotic lethality, antibiotic resistance is generally associated with drug target modification, enzymatic inactivation, and/or transport rather than metabolic processes. Evolution experiments of Escherichia coli rely on growth-dependent selection, which may provide a limited view of the antibiotic resistance landscape. We sequenced and analyzed E. coli adapted to representative antibiotics at increasingly heightened metabolic states. This revealed various underappreciated noncanonical genes, such as those related to central carbon and energy metabolism, which are implicated in antibiotic resistance. These metabolic alterations lead to lower basal respiration, which prevents antibiotic-mediated induction of tricarboxylic acid cycle activity, thus avoiding metabolic toxicity and minimizing drug lethality. Several of the identified metabolism-specific mutations are overrepresented in the genomes of >3500 clinical E. coli pathogens, indicating clinical relevance. 2021-10-27T19:53:09Z 2021-10-27T19:53:09Z 2021 2021-08-25T18:29:52Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/133494 en 10.1126/SCIENCE.ABA0862 Science Creative Commons Attribution 4.0 International license http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Lopatkin, Allison J Bening, Sarah C Manson, Abigail L Stokes, Jonathan M Kohanski, Michael A Badran, Ahmed H Earl, Ashlee M Cheney, Nicole J Yang, Jason H Collins, James J Clinically relevant mutations in core metabolic genes confer antibiotic resistance |
| title | Clinically relevant mutations in core metabolic genes confer antibiotic resistance |
| title_full | Clinically relevant mutations in core metabolic genes confer antibiotic resistance |
| title_fullStr | Clinically relevant mutations in core metabolic genes confer antibiotic resistance |
| title_full_unstemmed | Clinically relevant mutations in core metabolic genes confer antibiotic resistance |
| title_short | Clinically relevant mutations in core metabolic genes confer antibiotic resistance |
| title_sort | clinically relevant mutations in core metabolic genes confer antibiotic resistance |
| url | https://hdl.handle.net/1721.1/133494 |
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