High potency of sequential therapy with only beta-lactam antibiotics

  1. Aditi Batra
  2. Roderich Roemhild
  3. Emilie Rousseau
  4. Sören Franzenburg
  5. Stefan Niemann
  6. Hinrich Schulenburg  Is a corresponding author
  1. Kiel University, Germany
  2. University of Kiel, Germany
  3. Borstel Research Centre, Germany

Abstract

Evolutionary adaptation is a major source of antibiotic resistance in bacterial pathogens. Evolution-informed therapy aims to constrain resistance by accounting for bacterial evolvability. Sequential treatments with antibiotics that target different bacterial processes were previously shown to limit adaptation through genetic resistance trade-offs and negative hysteresis. Treatment with homogeneous sets of antibiotics is generally viewed to be disadvantageous, as it should rapidly lead to cross-resistance. We here challenged this assumption by determining the evolutionary response of Pseudomonas aeruginosa to experimental sequential treatments involving both heterogenous and homogeneous antibiotic sets. To our surprise, we found that fast switching between only β-lactam antibiotics resulted in increased extinction of bacterial populations. We demonstrate that extinction is favored by low rates of spontaneous resistance emergence and low levels of spontaneous cross-resistance among the antibiotics in sequence. The uncovered principles may help to guide the optimized use of available antibiotics in highly potent, evolution-informed treatment designs.

Data availability

Sequencing data have been deposited at NCBI under the BioProject number: PRJNA704789. All other data is provided in the supplementary source data files.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Aditi Batra

    Evolutionary Ecology and Genetics, Kiel University, Kiel, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Roderich Roemhild

    University of Kiel, Kiel, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9480-5261
  3. Emilie Rousseau

    Niemann Group, Borstel Research Centre, Borstel, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Sören Franzenburg

    Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Stefan Niemann

    Niemann Group, Borstel Research Centre, Borstel, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6604-0684
  6. Hinrich Schulenburg

    University of Kiel, Kiel, Germany
    For correspondence
    hschulenburg@zoologie.uni-kiel.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1413-913X

Funding

Deutsche Forschungsgemeinschaft (SCHU 1415/12)

  • Hinrich Schulenburg

Deutsche Forschungsgemeinschaft (EXC 2167-390884018)

  • Stefan Niemann
  • Hinrich Schulenburg

Deutsche Forschungsgemeinschaft (GRK 2501)

  • Stefan Niemann
  • Hinrich Schulenburg

Max-Planck-Gesellschaft (IMPRS Stipend)

  • Aditi Batra

Max-Planck-Gesellschaft (Fellowship)

  • Hinrich Schulenburg

Leibniz-Gemeinschaft (EvoLUNG)

  • Stefan Niemann
  • Hinrich Schulenburg

Deutsche Forschungsgemeinschaft (project 407495230)

  • Sören Franzenburg

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Vaughn S Cooper, University of Pittsburgh, United States

Publication history

  1. Received: March 29, 2021
  2. Accepted: July 22, 2021
  3. Accepted Manuscript published: July 28, 2021 (version 1)
  4. Version of Record published: August 31, 2021 (version 2)

Copyright

© 2021, Batra et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Aditi Batra
  2. Roderich Roemhild
  3. Emilie Rousseau
  4. Sören Franzenburg
  5. Stefan Niemann
  6. Hinrich Schulenburg
(2021)
High potency of sequential therapy with only beta-lactam antibiotics
eLife 10:e68876.
https://doi.org/10.7554/eLife.68876

Further reading

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    2. Epidemiology and Global Health
    3. Microbiology and Infectious Disease
    4. Genetics and Genomics
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