---
_id: '12261'
abstract:
- lang: eng
  text: 'Dose–response relationships are a general concept for quantitatively describing
    biological systems across multiple scales, from the molecular to the whole-cell
    level. A clinically relevant example is the bacterial growth response to antibiotics,
    which is routinely characterized by dose–response curves. The shape of the dose–response
    curve varies drastically between antibiotics and plays a key role in treatment,
    drug interactions, and resistance evolution. However, the mechanisms shaping the
    dose–response curve remain largely unclear. Here, we show in Escherichia coli
    that the distinctively shallow dose–response curve of the antibiotic trimethoprim
    is caused by a negative growth-mediated feedback loop: Trimethoprim slows growth,
    which in turn weakens the effect of this antibiotic. At the molecular level, this
    feedback is caused by the upregulation of the drug target dihydrofolate reductase
    (FolA/DHFR). We show that this upregulation is not a specific response to trimethoprim
    but follows a universal trend line that depends primarily on the growth rate,
    irrespective of its cause. Rewiring the feedback loop alters the dose–response
    curve in a predictable manner, which we corroborate using a mathematical model
    of cellular resource allocation and growth. Our results indicate that growth-mediated
    feedback loops may shape drug responses more generally and could be exploited
    to design evolutionary traps that enable selection against drug resistance.'
acknowledged_ssus:
- _id: M-Shop
acknowledgement: This work was in part supported by Human Frontier Science Program
  GrantRGP0042/2013, Marie Curie Career Integration Grant303507, AustrianScience Fund
  (FWF) Grant P27201-B22, and German Research Foundation(DFG) Collaborative Research
  Center (SFB)1310to TB. SAA was supportedby the European Union’s Horizon2020Research
  and Innovation Programunder the Marie Skłodowska-Curie Grant agreement No707352.
  We wouldlike to thank the Bollenbach group for regular fruitful discussions. We
  areparticularly thankful for the technical assistance of Booshini Fernando andfor
  discussions of the theoretical aspects with Gerrit Ansmann. We areindebted to Bor
  Kavˇciˇc for invaluable advice, help with setting up theluciferase-based growth
  monitoring system, and for sharing plasmids. Weacknowledge the IST Austria Miba
  Machine Shop for their support inbuilding a housing for the stacker of the plate
  reader, which enabled thehigh-throughput luciferase-based experiments. We are grateful
  to RosalindAllen, Bor Kavˇciˇc and Dor Russ for feedback on the manuscript. Open
  Accessfunding enabled and organized by Projekt DEAL.
article_number: e10490
article_processing_charge: No
article_type: original
author:
- first_name: Andreas
  full_name: Angermayr, Andreas
  id: 4677C796-F248-11E8-B48F-1D18A9856A87
  last_name: Angermayr
  orcid: 0000-0001-8619-2223
- first_name: Tin Yau
  full_name: Pang, Tin Yau
  last_name: Pang
- first_name: Guillaume
  full_name: Chevereau, Guillaume
  last_name: Chevereau
- first_name: Karin
  full_name: Mitosch, Karin
  id: 39B66846-F248-11E8-B48F-1D18A9856A87
  last_name: Mitosch
- first_name: Martin J
  full_name: Lercher, Martin J
  last_name: Lercher
- first_name: Mark Tobias
  full_name: Bollenbach, Mark Tobias
  id: 3E6DB97A-F248-11E8-B48F-1D18A9856A87
  last_name: Bollenbach
  orcid: 0000-0003-4398-476X
citation:
  ama: Angermayr A, Pang TY, Chevereau G, Mitosch K, Lercher MJ, Bollenbach MT. Growth‐mediated
    negative feedback shapes quantitative antibiotic response. <i>Molecular Systems
    Biology</i>. 2022;18(9). doi:<a href="https://doi.org/10.15252/msb.202110490">10.15252/msb.202110490</a>
  apa: Angermayr, A., Pang, T. Y., Chevereau, G., Mitosch, K., Lercher, M. J., &#38;
    Bollenbach, M. T. (2022). Growth‐mediated negative feedback shapes quantitative
    antibiotic response. <i>Molecular Systems Biology</i>. Embo Press. <a href="https://doi.org/10.15252/msb.202110490">https://doi.org/10.15252/msb.202110490</a>
  chicago: Angermayr, Andreas, Tin Yau Pang, Guillaume Chevereau, Karin Mitosch, Martin
    J Lercher, and Mark Tobias Bollenbach. “Growth‐mediated Negative Feedback Shapes
    Quantitative Antibiotic Response.” <i>Molecular Systems Biology</i>. Embo Press,
    2022. <a href="https://doi.org/10.15252/msb.202110490">https://doi.org/10.15252/msb.202110490</a>.
  ieee: A. Angermayr, T. Y. Pang, G. Chevereau, K. Mitosch, M. J. Lercher, and M.
    T. Bollenbach, “Growth‐mediated negative feedback shapes quantitative antibiotic
    response,” <i>Molecular Systems Biology</i>, vol. 18, no. 9. Embo Press, 2022.
  ista: Angermayr A, Pang TY, Chevereau G, Mitosch K, Lercher MJ, Bollenbach MT. 2022.
    Growth‐mediated negative feedback shapes quantitative antibiotic response. Molecular
    Systems Biology. 18(9), e10490.
  mla: Angermayr, Andreas, et al. “Growth‐mediated Negative Feedback Shapes Quantitative
    Antibiotic Response.” <i>Molecular Systems Biology</i>, vol. 18, no. 9, e10490,
    Embo Press, 2022, doi:<a href="https://doi.org/10.15252/msb.202110490">10.15252/msb.202110490</a>.
  short: A. Angermayr, T.Y. Pang, G. Chevereau, K. Mitosch, M.J. Lercher, M.T. Bollenbach,
    Molecular Systems Biology 18 (2022).
date_created: 2023-01-16T09:58:34Z
date_published: 2022-09-01T00:00:00Z
date_updated: 2023-08-04T09:51:49Z
day: '01'
ddc:
- '570'
department:
- _id: ToBo
doi: 10.15252/msb.202110490
external_id:
  isi:
  - '000856482800001'
file:
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  creator: dernst
  date_created: 2023-01-30T09:49:55Z
  date_updated: 2023-01-30T09:49:55Z
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file_date_updated: 2023-01-30T09:49:55Z
has_accepted_license: '1'
intvolume: '        18'
isi: 1
issue: '9'
keyword:
- Applied Mathematics
- Computational Theory and Mathematics
- General Agricultural and Biological Sciences
- General Immunology and Microbiology
- General Biochemistry
- Genetics and Molecular Biology
- Information Systems
language:
- iso: eng
month: '09'
oa: 1
oa_version: Published Version
publication: Molecular Systems Biology
publication_identifier:
  eissn:
  - 1744-4292
publication_status: published
publisher: Embo Press
quality_controlled: '1'
scopus_import: '1'
status: public
title: Growth‐mediated negative feedback shapes quantitative antibiotic response
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 18
year: '2022'
...