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

Erica J. Zheng; Ian W. Andrews; Alexandra T. Grote; Abigail L. Manson; Miguel A. Alcantar; Ashlee M. Earl; James J. Collins

doi:10.1038/s41467-022-30272-0

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

Erica J. Zheng, Ian W. Andrews, Alexandra T. Grote, Abigail L. Manson, Miguel A. Alcantar, Ashlee M. Earl, James J. Collins^*

^*Corresponding author for this work

Medicine, Infectious Diseases Division

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

Abstract

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.

Original language	English (US)
Article number	2525
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30272-0
State	Published - Dec 2022

Funding

We thank Sarah Bening, Melis Anahtar, Jackie Valeri, and Felix Wong for helpful discussions and suggestions. This work was supported by the Defense Threat Reduction Agency (HDTRA1-15-1-0051 to J.J.C.), NIH Grant Number R01-AI146194, the Broad Institute of MIT and Harvard, and a generous gift from A. and J. Bekenstein. This project has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Department of Health and Human Services, under Grant Number U19AI110818 to the Broad Institute. A.T.G. was funded by the Jane Coffin Childs Memorial Fund for Medical Research. M.A.A. was supported by a National Science Foundation graduate research fellowship (award no. 1122374).

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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title = "Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies",

abstract = "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.",

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AU - Zheng, Erica J.

AU - Andrews, Ian W.

AU - Grote, Alexandra T.

AU - Manson, Abigail L.

AU - Alcantar, Miguel A.

AU - Earl, Ashlee M.

AU - Collins, James J.

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N2 - 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.

AB - 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.

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

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