Robust antibiotic sensitization of pathogenic Pseudomonas aeruginosa via negative hysteresis in the cell envelope
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.
Authors
- Badri N. Dubey (ORCID: https://orcid.org/0000-0002-8626-8918)
- Leif Tüeffers
- Hinrich Schulenburg (ORCID: https://orcid.org/0000-0002-1413-913X)
- Marc Bramkamp (ORCID: https://orcid.org/0000-0002-7704-3266)
- Klaus F. Rabe (ORCID: https://orcid.org/0000-0002-7020-1401)
- Holger Sondermann (ORCID: https://orcid.org/0000-0003-2211-6234)
- Abigail Savietto Scholz
- Espen E. Groth (ORCID: https://orcid.org/0000-0003-0883-6366)
- Dennis Nurjadi (ORCID: https://orcid.org/0000-0002-1278-5939)
- Jan Rupp (ORCID: https://orcid.org/0000-0001-8722-1233)
- Barbara Kalsdorf
- Aditi Batra (ORCID: https://orcid.org/0000-0001-6910-3532)
- Roderich Roemhild (ORCID: https://orcid.org/0000-0001-9480-5261)
- Florian Buchholz (ORCID: https://orcid.org/0000-0003-3882-9132)
- Daniel Schütz
- Lina M. Upterworth (ORCID: https://orcid.org/0009-0000-2632-3957)
- Surajit Pal
- Samarpita Banerjee
- Kira Haas
- Dan I. Andersson
- Sören Franzenburg
Institutions
- Uppsala University (SE)
- Institute of Science and Technology Austria (AT)
- Deutsches Elektronen-Synchrotron DESY (DE)
- Hochschule für Angewandte Wissenschaften Kiel (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- University Hospital Schleswig-Holstein (DE)
- German Center for Infection Research (DE)
- Research Center Borstel - Leibniz Lung Center (DE)
- German Center for Lung Research (DE)
- LungenClinic Grosshansdorf (DE)
- Max Planck Institute for Evolutionary Biology (DE)
- Indian Institute of Technology Dharwad (IN)
- Centre for Structural Systems Biology (DE)
- Clinical Research Center Kiel (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-03-26
- DOI
- https://doi.org/10.1038/s41467-026-71178-5
- Primary Topic
- Bacterial Genetics and Biotechnology
- Type
- article
- Field-Weighted Citation Impact
- 0.00