---
DOAJ_listed: '1'
OA_place: publisher
OA_type: gold
PlanS_conform: '1'
_id: '21928'
abstract:
- lang: eng
text: Antibiotic combination in time and space is a key strategy to combat antimicrobial
resistance. The success of such treatment designs requires their robust efficacy
across treatment conditions and a pathogen’s genomic diversity. This study found
that an initial treatment with a β-lactam antibiotic causes robust cellular sensitization
towards an aminoglycoside antibiotic across the high-risk human pathogen Pseudomonas
aeruginosa, including resistant strains. This phenomenon of cellular sensitization,
termed negative hysteresis, is modulated by the Cpx envelope stress response system
and linked to membrane stress during growth. The increase in efficacy is achieved
through a β-lactam induced elevated cellular uptake of the subsequently administered
aminoglycoside. Negative hysteresis and the Cpx system are linked in several cases
to the expression of synergistic drug interactions, thus enhancing efficacy of
antibiotic combinations. Overall, our study identifies the phenomenon of negative
hysteresis as a robustly inducible phenotype and thus a unique focus for optimizing
antimicrobial therapy.
acknowledgement: "We are very grateful to S. Hernando-Amado (Madrid, Spain), C. Pál
(Szeged, Hungary), and T. Bollenbach (Cologne, Germany) for critical comments and
advice on the manuscript. We further thank D. Rogers, J. Summers (Ploen, Germany)
for guidance in allelic exchange, P. Rainey (Ploen, Germany) for providing the plasmids
and strains, then J. Lorenzen, K. Flinder, N. Steinbach, S. Butze (all Schulenburg
lab), and L. Kirchhoff (Rupp lab) for supporting the experimental work, and also
the Rupp and Schulenburg groups for general feedback. We are grateful for financial
support from the German Research Foundation within the Research and Training Group
2501 (RTG 2501) on Translational Evolutionary Research (project 4.2 to H.S.), within
the Excellence cluster Precision Medicine in chronic Inflammation (PMI; funding
under Germany’s Excellence Strategy EXC 2167-390884018, to B.K., K.R., J.R., H.S.),
within the Clinician Scientist Program in Evolutionary Medicine (CSEM) – project
number 413490537 (to EEG), and as part of the individual grants SCHU 1415/12-2 (to
H.S.) and BR-2915/7-1 (to M.B.). We are grateful for financial support from the
Swedish Research Council, project number 2021-02091 (to D.I.A.). We are also grateful
for financial support from the Max-Planck Society (Fellowship to H.S.), the Leibniz
Association within the Leibniz Science-Campus Evolutionary Medicine of the Lung
(EvoLUNG, to H.S.), and the project SKILLED funded by the DAMP foundation (to J.R.,
H.S.). This work was also supported by the ZMB Young Scientist award and the FWF
grant 10.55776/ESP219 (to R.R.) and the TransEvo Innovation prize (to F.B.). The
funders had no role in study design, data collection and interpretation, or the
decision to submit the work for publication. Open Access funding enabled and organized
by Projekt DEAL.\r\n"
article_number: '4487'
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Florian
full_name: Buchholz, Florian
last_name: Buchholz
- first_name: Lina M.
full_name: Upterworth, Lina M.
last_name: Upterworth
- first_name: Leif
full_name: Tueffers, Leif
last_name: Tueffers
- first_name: Espen E.
full_name: Groth, Espen E.
last_name: Groth
- first_name: Kira
full_name: Haas, Kira
last_name: Haas
- first_name: Daniel
full_name: Schütz, Daniel
last_name: Schütz
- first_name: Abigail
full_name: Savietto Scholz, Abigail
last_name: Savietto Scholz
- first_name: Aditi
full_name: Batra, Aditi
last_name: Batra
- first_name: Surajit
full_name: Pal, Surajit
last_name: Pal
- first_name: Samarpita
full_name: Banerjee, Samarpita
last_name: Banerjee
- first_name: Badri N.
full_name: Dubey, Badri N.
last_name: Dubey
- first_name: Sören
full_name: Franzenburg, Sören
last_name: Franzenburg
- first_name: Barbara
full_name: Kalsdorf, Barbara
last_name: Kalsdorf
- first_name: Klaus F.
full_name: Rabe, Klaus F.
last_name: Rabe
- first_name: Dennis
full_name: Nurjadi, Dennis
last_name: Nurjadi
- first_name: Jan
full_name: Rupp, Jan
last_name: Rupp
- first_name: Dan I.
full_name: Andersson, Dan I.
last_name: Andersson
- first_name: Holger
full_name: Sondermann, Holger
last_name: Sondermann
- first_name: Marc
full_name: Bramkamp, Marc
last_name: Bramkamp
- first_name: Roderich
full_name: Römhild, Roderich
id: 68E56E44-62B0-11EA-B963-444F3DDC885E
last_name: Römhild
orcid: 0000-0001-9480-5261
- first_name: Hinrich
full_name: Schulenburg, Hinrich
last_name: Schulenburg
citation:
ama: Buchholz F, Upterworth LM, Tueffers L, et al. Robust antibiotic sensitization
of pathogenic Pseudomonas aeruginosa via negative hysteresis in the cell envelope.
Nature Communications. 2026;17. doi:10.1038/s41467-026-71178-5
apa: Buchholz, F., Upterworth, L. M., Tueffers, L., Groth, E. E., Haas, K., Schütz,
D., … Schulenburg, H. (2026). Robust antibiotic sensitization of pathogenic Pseudomonas
aeruginosa via negative hysteresis in the cell envelope. Nature Communications.
Springer Nature. https://doi.org/10.1038/s41467-026-71178-5
chicago: Buchholz, Florian, Lina M. Upterworth, Leif Tueffers, Espen E. Groth, Kira
Haas, Daniel Schütz, Abigail Savietto Scholz, et al. “Robust Antibiotic Sensitization
of Pathogenic Pseudomonas Aeruginosa via Negative Hysteresis in the Cell Envelope.”
Nature Communications. Springer Nature, 2026. https://doi.org/10.1038/s41467-026-71178-5.
ieee: F. Buchholz et al., “Robust antibiotic sensitization of pathogenic
Pseudomonas aeruginosa via negative hysteresis in the cell envelope,” Nature
Communications, vol. 17. Springer Nature, 2026.
ista: Buchholz F, Upterworth LM, Tueffers L, Groth EE, Haas K, Schütz D, Savietto
Scholz A, Batra A, Pal S, Banerjee S, Dubey BN, Franzenburg S, Kalsdorf B, Rabe
KF, Nurjadi D, Rupp J, Andersson DI, Sondermann H, Bramkamp M, Römhild R, Schulenburg
H. 2026. Robust antibiotic sensitization of pathogenic Pseudomonas aeruginosa
via negative hysteresis in the cell envelope. Nature Communications. 17, 4487.
mla: Buchholz, Florian, et al. “Robust Antibiotic Sensitization of Pathogenic Pseudomonas
Aeruginosa via Negative Hysteresis in the Cell Envelope.” Nature Communications,
vol. 17, 4487, Springer Nature, 2026, doi:10.1038/s41467-026-71178-5.
short: F. Buchholz, L.M. Upterworth, L. Tueffers, E.E. Groth, K. Haas, D. Schütz,
A. Savietto Scholz, A. Batra, S. Pal, S. Banerjee, B.N. Dubey, S. Franzenburg,
B. Kalsdorf, K.F. Rabe, D. Nurjadi, J. Rupp, D.I. Andersson, H. Sondermann, M.
Bramkamp, R. Römhild, H. Schulenburg, Nature Communications 17 (2026).
corr_author: '1'
date_created: 2026-05-31T22:02:12Z
date_published: 2026-05-20T00:00:00Z
date_updated: 2026-06-02T07:14:35Z
day: '20'
ddc:
- '570'
department:
- _id: CaGu
doi: 10.1038/s41467-026-71178-5
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month: '05'
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project:
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grant_number: E219
name: Non-canonical antibiotic interactions
publication: Nature Communications
publication_identifier:
eissn:
- 2041-1723
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: Robust antibiotic sensitization of pathogenic Pseudomonas aeruginosa via negative
hysteresis in the cell envelope
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: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 17
year: '2026'
...