---
_id: '10812'
abstract:
- lang: eng
  text: Several promising strategies based on combining or cycling different antibiotics
    have been proposed to increase efficacy and counteract resistance evolution, but
    we still lack a deep understanding of the physiological responses and genetic
    mechanisms that underlie antibiotic interactions and the clinical applicability
    of these strategies. In antibiotic-exposed bacteria, the combined effects of physiological
    stress responses and emerging resistance mutations (occurring at different time
    scales) generate complex and often unpredictable dynamics. In this Review, we
    present our current understanding of bacterial cell physiology and genetics of
    responses to antibiotics. We emphasize recently discovered mechanisms of synergistic
    and antagonistic drug interactions, hysteresis in temporal interactions between
    antibiotics that arise from microbial physiology and interactions between antibiotics
    and resistance mutations that can cause collateral sensitivity or cross-resistance.
    We discuss possible connections between the different phenomena and indicate relevant
    research directions. A better and more unified understanding of drug and genetic
    interactions is likely to advance antibiotic therapy.
acknowledgement: The authors thank B. Kavčič and H. Schulenburg for constructive feedback
  on the manuscript.
article_processing_charge: No
article_type: review
author:
- first_name: Roderich
  full_name: Römhild, Roderich
  id: 68E56E44-62B0-11EA-B963-444F3DDC885E
  last_name: Römhild
  orcid: 0000-0001-9480-5261
- first_name: Mark Tobias
  full_name: Bollenbach, Mark Tobias
  id: 3E6DB97A-F248-11E8-B48F-1D18A9856A87
  last_name: Bollenbach
  orcid: 0000-0003-4398-476X
- first_name: Dan I.
  full_name: Andersson, Dan I.
  last_name: Andersson
citation:
  ama: Römhild R, Bollenbach MT, Andersson DI. The physiology and genetics of bacterial
    responses to antibiotic combinations. <i>Nature Reviews Microbiology</i>. 2022;20:478-490.
    doi:<a href="https://doi.org/10.1038/s41579-022-00700-5">10.1038/s41579-022-00700-5</a>
  apa: Römhild, R., Bollenbach, M. T., &#38; Andersson, D. I. (2022). The physiology
    and genetics of bacterial responses to antibiotic combinations. <i>Nature Reviews
    Microbiology</i>. Springer Nature. <a href="https://doi.org/10.1038/s41579-022-00700-5">https://doi.org/10.1038/s41579-022-00700-5</a>
  chicago: Römhild, Roderich, Mark Tobias Bollenbach, and Dan I. Andersson. “The Physiology
    and Genetics of Bacterial Responses to Antibiotic Combinations.” <i>Nature Reviews
    Microbiology</i>. Springer Nature, 2022. <a href="https://doi.org/10.1038/s41579-022-00700-5">https://doi.org/10.1038/s41579-022-00700-5</a>.
  ieee: R. Römhild, M. T. Bollenbach, and D. I. Andersson, “The physiology and genetics
    of bacterial responses to antibiotic combinations,” <i>Nature Reviews Microbiology</i>,
    vol. 20. Springer Nature, pp. 478–490, 2022.
  ista: Römhild R, Bollenbach MT, Andersson DI. 2022. The physiology and genetics
    of bacterial responses to antibiotic combinations. Nature Reviews Microbiology.
    20, 478–490.
  mla: Römhild, Roderich, et al. “The Physiology and Genetics of Bacterial Responses
    to Antibiotic Combinations.” <i>Nature Reviews Microbiology</i>, vol. 20, Springer
    Nature, 2022, pp. 478–90, doi:<a href="https://doi.org/10.1038/s41579-022-00700-5">10.1038/s41579-022-00700-5</a>.
  short: R. Römhild, M.T. Bollenbach, D.I. Andersson, Nature Reviews Microbiology
    20 (2022) 478–490.
date_created: 2022-03-04T04:33:49Z
date_published: 2022-08-01T00:00:00Z
date_updated: 2023-08-02T14:41:44Z
day: '01'
department:
- _id: CaGu
doi: 10.1038/s41579-022-00700-5
external_id:
  isi:
  - '000763891900001'
  pmid:
  - '35241807'
intvolume: '        20'
isi: 1
keyword:
- General Immunology and Microbiology
- Microbiology
- Infectious Diseases
language:
- iso: eng
month: '08'
oa_version: None
page: 478-490
pmid: 1
publication: Nature Reviews Microbiology
publication_identifier:
  eissn:
  - 1740-1534
  issn:
  - 1740-1526
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: The physiology and genetics of bacterial responses to antibiotic combinations
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 20
year: '2022'
...
---
_id: '9046'
acknowledgement: Our work was supported by the Swedish Research Council (grant 2017-01527)
  to DIA
article_number: e1009172
article_processing_charge: No
article_type: original
author:
- first_name: Roderich
  full_name: Römhild, Roderich
  id: 68E56E44-62B0-11EA-B963-444F3DDC885E
  last_name: Römhild
  orcid: 0000-0001-9480-5261
- first_name: Dan I.
  full_name: Andersson, Dan I.
  last_name: Andersson
citation:
  ama: Römhild R, Andersson DI. Mechanisms and therapeutic potential of collateral
    sensitivity to antibiotics. <i>PLoS Pathogens</i>. 2021;17(1). doi:<a href="https://doi.org/10.1371/journal.ppat.1009172">10.1371/journal.ppat.1009172</a>
  apa: Römhild, R., &#38; Andersson, D. I. (2021). Mechanisms and therapeutic potential
    of collateral sensitivity to antibiotics. <i>PLoS Pathogens</i>. Public Library
    of Science. <a href="https://doi.org/10.1371/journal.ppat.1009172">https://doi.org/10.1371/journal.ppat.1009172</a>
  chicago: Römhild, Roderich, and Dan I. Andersson. “Mechanisms and Therapeutic Potential
    of Collateral Sensitivity to Antibiotics.” <i>PLoS Pathogens</i>. Public Library
    of Science, 2021. <a href="https://doi.org/10.1371/journal.ppat.1009172">https://doi.org/10.1371/journal.ppat.1009172</a>.
  ieee: R. Römhild and D. I. Andersson, “Mechanisms and therapeutic potential of collateral
    sensitivity to antibiotics,” <i>PLoS Pathogens</i>, vol. 17, no. 1. Public Library
    of Science, 2021.
  ista: Römhild R, Andersson DI. 2021. Mechanisms and therapeutic potential of collateral
    sensitivity to antibiotics. PLoS Pathogens. 17(1), e1009172.
  mla: Römhild, Roderich, and Dan I. Andersson. “Mechanisms and Therapeutic Potential
    of Collateral Sensitivity to Antibiotics.” <i>PLoS Pathogens</i>, vol. 17, no.
    1, e1009172, Public Library of Science, 2021, doi:<a href="https://doi.org/10.1371/journal.ppat.1009172">10.1371/journal.ppat.1009172</a>.
  short: R. Römhild, D.I. Andersson, PLoS Pathogens 17 (2021).
date_created: 2021-01-31T23:01:21Z
date_published: 2021-01-14T00:00:00Z
date_updated: 2023-08-07T13:36:55Z
day: '14'
ddc:
- '570'
department:
- _id: CaGu
doi: 10.1371/journal.ppat.1009172
external_id:
  isi:
  - '000610190400007'
  pmid:
  - '33444399'
file:
- access_level: open_access
  checksum: d745d7f8fcbb9b95fea16a36f94dee31
  content_type: application/pdf
  creator: dernst
  date_created: 2021-02-03T12:13:03Z
  date_updated: 2021-02-03T12:13:03Z
  file_id: '9070'
  file_name: 2021_PlosPathogens_Roemhild.pdf
  file_size: 570066
  relation: main_file
  success: 1
file_date_updated: 2021-02-03T12:13:03Z
has_accepted_license: '1'
intvolume: '        17'
isi: 1
issue: '1'
language:
- iso: eng
month: '01'
oa: 1
oa_version: Published Version
pmid: 1
publication: PLoS Pathogens
publication_identifier:
  eissn:
  - '15537374'
  issn:
  - '15537366'
publication_status: published
publisher: Public Library of Science
quality_controlled: '1'
scopus_import: '1'
status: public
title: Mechanisms and therapeutic potential of collateral sensitivity to antibiotics
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: 17
year: '2021'
...
---
_id: '9746'
abstract:
- lang: eng
  text: 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.
acknowledgement: We would like to thank Leif Tueffers and João Botelho for discussions
  and suggestions as well as Kira Haas and Julia Bunk for technical support. We acknowledge
  financial support from the German Science Foundation (grant SCHU 1415/12-2 to HS,
  and funding under Germany’s Excellence Strategy EXC 2167–390884018 as well as the
  Research Training Group 2501 TransEvo to HS and SN), the Max Planck Society (IMPRS
  scholarship to AB; Max-Planck fellowship to HS), and the Leibniz Science Campus
  Evolutionary Medicine of the Lung (EvoLUNG, to HS and SN). This work was further
  supported by the German Science Foundation Research Infrastructure NGS_CC (project
  407495230) as part of the Next Generation Sequencing Competence Network (project
  423957469). NGS analyses were carried out at the Competence Centre for Genomic Analysis
  Kiel (CCGA Kiel).
article_number: e68876
article_processing_charge: No
article_type: original
author:
- first_name: Aditi
  full_name: Batra, Aditi
  last_name: Batra
- first_name: Roderich
  full_name: Römhild, Roderich
  id: 68E56E44-62B0-11EA-B963-444F3DDC885E
  last_name: Römhild
  orcid: 0000-0001-9480-5261
- first_name: Emilie
  full_name: Rousseau, Emilie
  last_name: Rousseau
- first_name: Sören
  full_name: Franzenburg, Sören
  last_name: Franzenburg
- first_name: Stefan
  full_name: Niemann, Stefan
  last_name: Niemann
- first_name: Hinrich
  full_name: Schulenburg, Hinrich
  last_name: Schulenburg
citation:
  ama: Batra A, Römhild R, Rousseau E, Franzenburg S, Niemann S, Schulenburg H. High
    potency of sequential therapy with only beta-lactam antibiotics. <i>eLife</i>.
    2021;10. doi:<a href="https://doi.org/10.7554/elife.68876">10.7554/elife.68876</a>
  apa: Batra, A., Römhild, R., Rousseau, E., Franzenburg, S., Niemann, S., &#38; Schulenburg,
    H. (2021). High potency of sequential therapy with only beta-lactam antibiotics.
    <i>ELife</i>. eLife Sciences Publications. <a href="https://doi.org/10.7554/elife.68876">https://doi.org/10.7554/elife.68876</a>
  chicago: Batra, Aditi, Roderich Römhild, Emilie Rousseau, Sören Franzenburg, Stefan
    Niemann, and Hinrich Schulenburg. “High Potency of Sequential Therapy with Only
    Beta-Lactam Antibiotics.” <i>ELife</i>. eLife Sciences Publications, 2021. <a
    href="https://doi.org/10.7554/elife.68876">https://doi.org/10.7554/elife.68876</a>.
  ieee: A. Batra, R. Römhild, E. Rousseau, S. Franzenburg, S. Niemann, and H. Schulenburg,
    “High potency of sequential therapy with only beta-lactam antibiotics,” <i>eLife</i>,
    vol. 10. eLife Sciences Publications, 2021.
  ista: Batra A, Römhild R, Rousseau E, Franzenburg S, Niemann S, Schulenburg H. 2021.
    High potency of sequential therapy with only beta-lactam antibiotics. eLife. 10,
    e68876.
  mla: Batra, Aditi, et al. “High Potency of Sequential Therapy with Only Beta-Lactam
    Antibiotics.” <i>ELife</i>, vol. 10, e68876, eLife Sciences Publications, 2021,
    doi:<a href="https://doi.org/10.7554/elife.68876">10.7554/elife.68876</a>.
  short: A. Batra, R. Römhild, E. Rousseau, S. Franzenburg, S. Niemann, H. Schulenburg,
    ELife 10 (2021).
date_created: 2021-07-28T13:36:57Z
date_published: 2021-07-28T00:00:00Z
date_updated: 2023-08-11T10:26:29Z
day: '28'
department:
- _id: CaGu
doi: 10.7554/elife.68876
external_id:
  isi:
  - '000692027800001'
  pmid:
  - '34318749'
intvolume: '        10'
isi: 1
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://doi.org/10.7554/eLife.68876
month: '07'
oa: 1
oa_version: Published Version
pmid: 1
publication: eLife
publication_identifier:
  eissn:
  - 2050-084X
publication_status: published
publisher: eLife Sciences Publications
quality_controlled: '1'
scopus_import: '1'
status: public
title: High potency of sequential therapy with only beta-lactam antibiotics
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 10
year: '2021'
...