@article{5f0cc54d9e534f79ab955b79cb4e5a2f,
title = "Clinically relevant mutations in core metabolic genes confer antibiotic resistance",
abstract = "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.",
author = "Lopatkin, {Allison J.} and Bening, {Sarah C.} and Manson, {Abigail L.} and Stokes, {Jonathan M.} and Kohanski, {Michael A.} and Badran, {Ahmed H.} and Earl, {Ashlee M.} and Cheney, {Nicole J.} and Yang, {Jason H.} and Collins, {James J.}",
note = "Funding Information: Funding: This work was supported by the Defense Threat Reduction Agency (HDTRA1-15-1-0051), the National Institutes of Health (R00GM118907, R01AI146194), the National Institutes of Health Director{\textquoteright}s Early Independence Award (DP5-OD-024590), the National Science Foundation Graduate Research Fellowship Program (1122374), the Broad Institute of MIT and Harvard, and a generous gift from Anita and Josh Bekenstein. This work has also been funded in part with funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under grant no. U19AI110818 to the Broad Institute Publisher Copyright: {\textcopyright} 2021 American Association for the Advancement of Science. All rights reserved.",
year = "2021",
month = feb,
day = "19",
doi = "10.1126/science.aba0862",
language = "English (US)",
volume = "371",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6531",
}