Cargando…

Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies

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....

Descripción completa

Detalles Bibliográficos
Autores principales: Zheng, Erica J., Andrews, Ian W., Grote, Alexandra T., Manson, Abigail L., Alcantar, Miguel A., Earl, Ashlee M., Collins, James J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9085803/
https://www.ncbi.nlm.nih.gov/pubmed/35534481
http://dx.doi.org/10.1038/s41467-022-30272-0
_version_ 1784703899553234944
author Zheng, Erica J.
Andrews, Ian W.
Grote, Alexandra T.
Manson, Abigail L.
Alcantar, Miguel A.
Earl, Ashlee M.
Collins, James J.
author_facet 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 PubMed
description 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 E. coli involving deletion of the sodium-proton antiporter gene nhaA, 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.
format Online
Article
Text
id pubmed-9085803
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-90858032022-05-11 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. Nat Commun Article 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 E. coli involving deletion of the sodium-proton antiporter gene nhaA, 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. Nature Publishing Group UK 2022-05-09 /pmc/articles/PMC9085803/ /pubmed/35534481 http://dx.doi.org/10.1038/s41467-022-30272-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9085803/
https://www.ncbi.nlm.nih.gov/pubmed/35534481
http://dx.doi.org/10.1038/s41467-022-30272-0
work_keys_str_mv AT zhengericaj modulatingtheevolutionarytrajectoryoftoleranceusingantibioticswithdifferentmetabolicdependencies
AT andrewsianw modulatingtheevolutionarytrajectoryoftoleranceusingantibioticswithdifferentmetabolicdependencies
AT grotealexandrat modulatingtheevolutionarytrajectoryoftoleranceusingantibioticswithdifferentmetabolicdependencies
AT mansonabigaill modulatingtheevolutionarytrajectoryoftoleranceusingantibioticswithdifferentmetabolicdependencies
AT alcantarmiguela modulatingtheevolutionarytrajectoryoftoleranceusingantibioticswithdifferentmetabolicdependencies
AT earlashleem modulatingtheevolutionarytrajectoryoftoleranceusingantibioticswithdifferentmetabolicdependencies
AT collinsjamesj modulatingtheevolutionarytrajectoryoftoleranceusingantibioticswithdifferentmetabolicdependencies