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Clinically relevant mutations in core metabolic genes confer antibiotic resistance
Name
nihms-1717391.pdf
Description
Accepted version
Size
1.46 MB
Format
Adobe PDF
Checksum (MD5)
6fd69b733ef86a2388fa2078e37b9f5f
Author(s)
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
Date Issued
2021
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Version
Author's final manuscript
Abstract
© 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.
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
10.1126/SCIENCE.ABA0862
