Robust antibiotic sensitization of pathogenic Pseudomonas aeruginosa via negative hysteresis in the cell envelope

article Robust antibiotic sensitization of pathogenic Pseudomonas aeruginosa via negative hysteresis in the cell envelope published yes Florian Buchholz author Lina M. Upterworth author Leif Tueffers author Espen E. Groth author Kira Haas author Daniel Schütz author Abigail Savietto Scholz author Aditi Batra author Surajit Pal author Samarpita Banerjee author Badri N. Dubey author Sören Franzenburg author Barbara Kalsdorf author Klaus F. Rabe author Dennis Nurjadi author Jan Rupp author Dan I. Andersson author Holger Sondermann author Marc Bramkamp author Roderich Römhild author 68E56E44-62B0-11EA-B963-444F3DDC885E0000-0001-9480-5261 Hinrich Schulenburg author CaGu department Non-canonical antibiotic interactions project 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. https://research-explorer.ista.ac.at/download/21928/21936/2026_NatureComm_Buchholz.pdf application/pdfno Springer Nature2026 eng Nature Communications 2041-172310.1038/s41467-026-71178-5 17 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:<a href="https://doi.org/10.1038/s41467-026-71178-5">10.1038/s41467-026-71178-5</a>. 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. 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. 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. <a href="https://doi.org/10.1038/s41467-026-71178-5">https://doi.org/10.1038/s41467-026-71178-5</a>. 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. <a href="https://doi.org/10.1038/s41467-026-71178-5">https://doi.org/10.1038/s41467-026-71178-5</a> 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). 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:<a href="https://doi.org/10.1038/s41467-026-71178-5">10.1038/s41467-026-71178-5</a> 219282026-05-31T22:02:12Z2026-06-02T07:14:35Z