IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-30272-0.html
   My bibliography  Save this article

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

Author

Listed:
  • Erica J. Zheng

    (Harvard University
    Broad Institute of MIT and Harvard)

  • Ian W. Andrews

    (Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology)

  • Alexandra T. Grote

    (Broad Institute of MIT and Harvard)

  • Abigail L. Manson

    (Broad Institute of MIT and Harvard)

  • Miguel A. Alcantar

    (Massachusetts Institute of Technology)

  • Ashlee M. Earl

    (Broad Institute of MIT and Harvard)

  • James J. Collins

    (Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology
    Harvard University
    Harvard-MIT Program in Health Sciences and Technology)

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.

Suggested Citation

  • Erica J. Zheng & Ian W. Andrews & Alexandra T. Grote & Abigail L. Manson & Miguel A. Alcantar & Ashlee M. Earl & James J. Collins, 2022. "Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30272-0
    DOI: 10.1038/s41467-022-30272-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-30272-0
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-30272-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Niclas Nordholt & Orestis Kanaris & Selina B. I. Schmidt & Frank Schreiber, 2021. "Persistence against benzalkonium chloride promotes rapid evolution of tolerance during periodic disinfection," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Bram Van den Bergh & Hannah Schramke & Joran Elie Michiels & Tom E. P. Kimkes & Jakub Leszek Radzikowski & Johannes Schimpf & Silke R. Vedelaar & Sabrina Burschel & Liselot Dewachter & Nikola Lončar &, 2022. "Mutations in respiratory complex I promote antibiotic persistence through alterations in intracellular acidity and protein synthesis," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Ofer Fridman & Amir Goldberg & Irine Ronin & Noam Shoresh & Nathalie Q. Balaban, 2014. "Optimization of lag time underlies antibiotic tolerance in evolved bacterial populations," Nature, Nature, vol. 513(7518), pages 418-421, September.
    4. Erik Bakkeren & Jana S. Huisman & Stefan A. Fattinger & Annika Hausmann & Markus Furter & Adrian Egli & Emma Slack & Mikael E. Sellin & Sebastian Bonhoeffer & Roland R. Regoes & Médéric Diard & Wolf-D, 2019. "Salmonella persisters promote the spread of antibiotic resistance plasmids in the gut," Nature, Nature, vol. 573(7773), pages 276-280, September.
    5. Adrian Kordes & Matthias Preusse & Sven D. Willger & Peter Braubach & Danny Jonigk & Axel Haverich & Gregor Warnecke & Susanne Häussler, 2019. "Genetically diverse Pseudomonas aeruginosa populations display similar transcriptomic profiles in a cystic fibrosis explanted lung," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    6. Vanina Dengler Haunreiter & Mathilde Boumasmoud & Nicola Häffner & Dennis Wipfli & Nadja Leimer & Carole Rachmühl & Denise Kühnert & Yvonne Achermann & Reinhard Zbinden & Stefano Benussi & Clement Vul, 2019. "In-host evolution of Staphylococcus epidermidis in a pacemaker-associated endocarditis resulting in increased antibiotic tolerance," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    7. Theresa C. Barrett & Wendy W. K. Mok & Allison M. Murawski & Mark P. Brynildsen, 2019. "Enhanced antibiotic resistance development from fluoroquinolone persisters after a single exposure to antibiotic," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Amir Arastehfar & Farnaz Daneshnia & Nathaly Cabrera & Suyapa Penalva-Lopez & Jansy Sarathy & Matthew Zimmerman & Erika Shor & David S. Perlin, 2023. "Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Alexandr Safatov & Irina Andreeva & Galina Buryak & Olesia Ohlopkova & Sergei Olkin & Larisa Puchkova & Irina Reznikova & Nadezda Solovyanova & Boris Belan & Mikhail Panchenko & Denis Simonenkov, 2020. "How Has the Hazard to Humans of Microorganisms Found in Atmospheric Aerosol in the South of Western Siberia Changed over 10 Years?," IJERPH, MDPI, vol. 17(5), pages 1-19, March.
    2. Marianne Bauer & Isabella R Graf & Vudtiwat Ngampruetikorn & Greg J Stephens & Erwin Frey, 2017. "Exploiting ecology in drug pulse sequences in favour of population reduction," PLOS Computational Biology, Public Library of Science, vol. 13(9), pages 1-17, September.
    3. Sourav Chowdhury & Daniel C. Zielinski & Christopher Dalldorf & Joao V. Rodrigues & Bernhard O. Palsson & Eugene I. Shakhnovich, 2023. "Empowering drug off-target discovery with metabolic and structural analysis," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Niclas Nordholt & Orestis Kanaris & Selina B. I. Schmidt & Frank Schreiber, 2021. "Persistence against benzalkonium chloride promotes rapid evolution of tolerance during periodic disinfection," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    5. José Camacho Mateu & Matteo Sireci & Miguel A Muñoz, 2021. "Phenotypic-dependent variability and the emergence of tolerance in bacterial populations," PLOS Computational Biology, Public Library of Science, vol. 17(9), pages 1-28, September.
    6. Yinyin Ma & Josep Ramoneda & David R. Johnson, 2023. "Timing of antibiotic administration determines the spread of plasmid-encoded antibiotic resistance during microbial range expansion," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    7. Alexander Sturm & Grzegorz Jóźwiak & Marta Pla Verge & Laura Munch & Gino Cathomen & Anthony Vocat & Amanda Luraschi-Eggemann & Clara Orlando & Katja Fromm & Eric Delarze & Michał Świątkowski & Grzego, 2024. "Accurate and rapid antibiotic susceptibility testing using a machine learning-assisted nanomotion technology platform," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    8. Jessica A Lee & Siavash Riazi & Shahla Nemati & Jannell V Bazurto & Andreas E Vasdekis & Benjamin J Ridenhour & Christopher H Remien & Christopher J Marx, 2019. "Microbial phenotypic heterogeneity in response to a metabolic toxin: Continuous, dynamically shifting distribution of formaldehyde tolerance in Methylobacterium extorquens populations," PLOS Genetics, Public Library of Science, vol. 15(11), pages 1-38, November.
    9. Mehrose Ahmad & Hannah Prensky & Jacqueline Balestrieri & Shahd ElNaggar & Angela Gomez-Simmonds & Anne-Catrin Uhlemann & Beth Traxler & Abhyudai Singh & Allison J. Lopatkin, 2023. "Tradeoff between lag time and growth rate drives the plasmid acquisition cost," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    10. Elwood A. Mullins & Jonathan Dorival & Gong-Li Tang & Dale L. Boger & Brandt F. Eichman, 2021. "Structural evolution of a DNA repair self-resistance mechanism targeting genotoxic secondary metabolites," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    11. Horvath, Denis & Brutovsky, Branislav, 2016. "Etiology of phenotype switching strategy in time varying stochastic environment," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 462(C), pages 455-468.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30272-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.