[{"doi":"10.1038/s41467-026-71178-5","file":[{"checksum":"aa29f8806908dc0469dff21e2d5ad01f","file_size":1276166,"file_name":"2026_NatureComm_Buchholz.pdf","date_updated":"2026-06-02T07:11:12Z","creator":"dernst","access_level":"open_access","file_id":"21936","date_created":"2026-06-02T07:11:12Z","content_type":"application/pdf","success":1,"relation":"main_file"}],"publication_identifier":{"eissn":["2041-1723"]},"quality_controlled":"1","license":"https://creativecommons.org/licenses/by/4.0/","corr_author":"1","department":[{"_id":"CaGu"}],"OA_place":"publisher","OA_type":"gold","fulldoi":"https://doi.org/10.1038/s41467-026-71178-5","date_published":"2026-05-20T00:00:00Z","has_accepted_license":"1","status":"public","file_date_updated":"2026-06-02T07:11:12Z","oa_version":"Published Version","_id":"21928","scopus_import":"1","PlanS_conform":"1","month":"05","ddc":["570"],"DOAJ_listed":"1","publication_status":"published","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication":"Nature Communications","language":[{"iso":"eng"}],"type":"journal_article","publisher":"Springer Nature","year":"2026","date_created":"2026-05-31T22:02:12Z","article_processing_charge":"Yes (via OA deal)","oa":1,"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","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)"},"article_type":"original","article_number":"4487","volume":17,"citation":{"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.","ieee":"F. Buchholz <i>et al.</i>, “Robust antibiotic sensitization of pathogenic Pseudomonas aeruginosa via negative hysteresis in the cell envelope,” <i>Nature Communications</i>, vol. 17. Springer Nature, 2026.","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. <i>Nature Communications</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41467-026-71178-5\">https://doi.org/10.1038/s41467-026-71178-5</a>","mla":"Buchholz, Florian, et al. “Robust Antibiotic Sensitization of Pathogenic Pseudomonas Aeruginosa via Negative Hysteresis in the Cell Envelope.” <i>Nature Communications</i>, 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>.","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).","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.” <i>Nature Communications</i>. Springer Nature, 2026. <a href=\"https://doi.org/10.1038/s41467-026-71178-5\">https://doi.org/10.1038/s41467-026-71178-5</a>.","ama":"Buchholz F, Upterworth LM, Tueffers L, et al. Robust antibiotic sensitization of pathogenic Pseudomonas aeruginosa via negative hysteresis in the cell envelope. <i>Nature Communications</i>. 2026;17. doi:<a href=\"https://doi.org/10.1038/s41467-026-71178-5\">10.1038/s41467-026-71178-5</a>"},"project":[{"grant_number":"E219","_id":"bd6f94d1-d553-11ed-ba76-ae9f07250f74","name":"Non-canonical antibiotic interactions"}],"intvolume":"        17","day":"20","date_updated":"2026-06-02T07:14:35Z","title":"Robust antibiotic sensitization of pathogenic Pseudomonas aeruginosa via negative hysteresis in the cell envelope","author":[{"first_name":"Florian","last_name":"Buchholz","full_name":"Buchholz, Florian"},{"full_name":"Upterworth, Lina M.","first_name":"Lina M.","last_name":"Upterworth"},{"last_name":"Tueffers","first_name":"Leif","full_name":"Tueffers, Leif"},{"full_name":"Groth, Espen E.","first_name":"Espen E.","last_name":"Groth"},{"full_name":"Haas, Kira","first_name":"Kira","last_name":"Haas"},{"last_name":"Schütz","first_name":"Daniel","full_name":"Schütz, Daniel"},{"first_name":"Abigail","last_name":"Savietto Scholz","full_name":"Savietto Scholz, Abigail"},{"first_name":"Aditi","last_name":"Batra","full_name":"Batra, Aditi"},{"first_name":"Surajit","last_name":"Pal","full_name":"Pal, Surajit"},{"full_name":"Banerjee, Samarpita","first_name":"Samarpita","last_name":"Banerjee"},{"full_name":"Dubey, Badri N.","first_name":"Badri N.","last_name":"Dubey"},{"full_name":"Franzenburg, Sören","last_name":"Franzenburg","first_name":"Sören"},{"full_name":"Kalsdorf, Barbara","first_name":"Barbara","last_name":"Kalsdorf"},{"first_name":"Klaus F.","last_name":"Rabe","full_name":"Rabe, Klaus F."},{"full_name":"Nurjadi, Dennis","first_name":"Dennis","last_name":"Nurjadi"},{"last_name":"Rupp","first_name":"Jan","full_name":"Rupp, Jan"},{"full_name":"Andersson, Dan I.","first_name":"Dan I.","last_name":"Andersson"},{"full_name":"Sondermann, Holger","first_name":"Holger","last_name":"Sondermann"},{"full_name":"Bramkamp, Marc","last_name":"Bramkamp","first_name":"Marc"},{"first_name":"Roderich","id":"68E56E44-62B0-11EA-B963-444F3DDC885E","last_name":"Römhild","full_name":"Römhild, Roderich","orcid":"0000-0001-9480-5261"},{"last_name":"Schulenburg","first_name":"Hinrich","full_name":"Schulenburg, Hinrich"}],"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."}]},{"has_accepted_license":"1","date_published":"2025-04-15T00:00:00Z","file_date_updated":"2025-06-24T07:27:43Z","status":"public","issue":"15","pmid":1,"doi":"10.1073/pnas.2413709122","publication_identifier":{"eissn":["1091-6490"],"issn":["0027-8424"]},"file":[{"file_id":"19888","access_level":"open_access","creator":"dernst","date_updated":"2025-06-24T07:27:43Z","file_name":"2025_PNAS_Jain.pdf","checksum":"115a687f40009660eb4b38b4f6559d41","file_size":2949523,"relation":"main_file","success":1,"content_type":"application/pdf","date_created":"2025-06-24T07:27:43Z"}],"corr_author":"1","acknowledged_ssus":[{"_id":"Bio"}],"quality_controlled":"1","department":[{"_id":"CaGu"},{"_id":"Bio"},{"_id":"FyKo"},{"_id":"GaTk"}],"OA_place":"publisher","OA_type":"hybrid","fulldoi":"https://doi.org/10.1073/pnas.2413709122","related_material":{"link":[{"description":"News on ISTA website","url":"https://ista.ac.at/en/news/clockwork-just-for-antibiotic-resistance/","relation":"press_release"}],"record":[{"relation":"research_data","id":"19294","status":"public"}]},"publication":"Proceedings of the National Academy of Sciences","language":[{"iso":"eng"}],"publication_status":"published","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publisher":"National Academy of Sciences","type":"journal_article","isi":1,"_id":"19626","scopus_import":"1","oa_version":"Published Version","ddc":["570"],"month":"04","oa":1,"external_id":{"pmid":["40193613"],"isi":["001471235200001"]},"acknowledgement":"K.J. thanks B. Wu, I. Tomanek, K. Tomasek for detailed discussions on the manuscript, all other members from the Guet laboratory for valuable feedback, R. Chait, & Imaging and Optics Facility, Institute of Science and Technology Austria for helping with microscopy, Dr. Sudha Rao and Dr. Raja Mugasimangalam, Genotypic Technology India for allowing time off to address the revisions. K.J. acknowledges Institute of Science and Technology fellowship IC1006FELL02, R.H. was supported in part by Chan Zuckerberg Initiative and Donor Advised-Fund grant 2020-225401 (https://doi.org/10.37921/120055ratwvi), O.O.B. acknowledges Fonds Zur Förderung der Wissenschaftlichen Forschung (FWF) Grant ESP253-B, R.R. acknowledges FWF Grant 10.55776/ESP219, C.C.G. acknowledges FWF I5127-B.","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)"},"APC_amount":"5949 EUR","article_type":"original","year":"2025","date_created":"2025-04-27T22:02:13Z","article_processing_charge":"Yes (in subscription journal)","date_updated":"2026-05-20T08:33:08Z","title":"Pulsatile basal gene expression as a fitness determinant in bacteria","author":[{"first_name":"Kirti","last_name":"Jain","id":"330F0278-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-3809-0449","full_name":"Jain, Kirti"},{"first_name":"Robert","last_name":"Hauschild","id":"4E01D6B4-F248-11E8-B48F-1D18A9856A87","full_name":"Hauschild, Robert","orcid":"0000-0001-9843-3522"},{"full_name":"Bochkareva, Olga","orcid":"0000-0003-1006-6639","last_name":"Bochkareva","id":"C4558D3C-6102-11E9-A62E-F418E6697425","first_name":"Olga"},{"first_name":"Roderich","last_name":"Römhild","id":"68E56E44-62B0-11EA-B963-444F3DDC885E","full_name":"Römhild, Roderich","orcid":"0000-0001-9480-5261"},{"orcid":"0000-0002-6699-1455","full_name":"Tkačik, Gašper","last_name":"Tkačik","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","first_name":"Gašper"},{"full_name":"Guet, Calin C","orcid":"0000-0001-6220-2052","first_name":"Calin C","last_name":"Guet","id":"47F8433E-F248-11E8-B48F-1D18A9856A87"}],"abstract":[{"text":"Active regulation of gene expression, orchestrated by complex interactions of activators and repressors at promoters, controls the fate of organisms. In contrast, basal expression at uninduced promoters is considered to be a dynamically inert mode of nonfunctional “promoter leakiness,” merely a byproduct of transcriptional regulation. Here, we investigate the basal expression mode of the mar operon, the main regulator of intrinsic multiple antibiotic resistance in Escherichia coli, and link its dynamic properties to the noncanonical, yet highly conserved start codon of marR across Enterobacteriaceae. Real-time, single-cell measurements across tens of generations reveal that basal expression consists of rare stochastic gene expression pulses, which maximize variability in wildtype and, surprisingly, transiently accelerate cellular elongation rates. Competition experiments show that basal expression confers fitness advantages to wildtype across several transitions between exponential and stationary growth by shortening lag times. The dynamically rich basal expression of the mar operon has likely been evolutionarily maintained for its role in growth homeostasis of Enterobacteria within the gut environment, thereby allowing other ancillary gene regulatory roles to evolve, e.g., control of costly-to-induce multidrug efflux pumps. Understanding the complex selection forces governing genetic systems involved in intrinsic multidrug resistance is crucial for effective public health measures.","lang":"eng"}],"article_number":"e2413709122","intvolume":"       122","project":[{"grant_number":"CZI01","_id":"c08e9ad1-5a5b-11eb-8a69-9d1cf3b07473","name":"Tools for automation and feedback microscopy"},{"grant_number":"E219","name":"Non-canonical antibiotic interactions","_id":"bd6f94d1-d553-11ed-ba76-ae9f07250f74"},{"grant_number":"I05127","name":"Evolutionary analysis of gene regulation","_id":"34e076d6-11ca-11ed-8bc3-aec76c41a181"}],"citation":{"ama":"Jain K, Hauschild R, Bochkareva O, Römhild R, Tkačik G, Guet CC. Pulsatile basal gene expression as a fitness determinant in bacteria. <i>Proceedings of the National Academy of Sciences</i>. 2025;122(15). doi:<a href=\"https://doi.org/10.1073/pnas.2413709122\">10.1073/pnas.2413709122</a>","chicago":"Jain, Kirti, Robert Hauschild, Olga Bochkareva, Roderich Römhild, Gašper Tkačik, and Calin C Guet. “Pulsatile Basal Gene Expression as a Fitness Determinant in Bacteria.” <i>Proceedings of the National Academy of Sciences</i>. National Academy of Sciences, 2025. <a href=\"https://doi.org/10.1073/pnas.2413709122\">https://doi.org/10.1073/pnas.2413709122</a>.","mla":"Jain, Kirti, et al. “Pulsatile Basal Gene Expression as a Fitness Determinant in Bacteria.” <i>Proceedings of the National Academy of Sciences</i>, vol. 122, no. 15, e2413709122, National Academy of Sciences, 2025, doi:<a href=\"https://doi.org/10.1073/pnas.2413709122\">10.1073/pnas.2413709122</a>.","short":"K. Jain, R. Hauschild, O. Bochkareva, R. Römhild, G. Tkačik, C.C. Guet, Proceedings of the National Academy of Sciences 122 (2025).","ieee":"K. Jain, R. Hauschild, O. Bochkareva, R. Römhild, G. Tkačik, and C. C. Guet, “Pulsatile basal gene expression as a fitness determinant in bacteria,” <i>Proceedings of the National Academy of Sciences</i>, vol. 122, no. 15. National Academy of Sciences, 2025.","apa":"Jain, K., Hauschild, R., Bochkareva, O., Römhild, R., Tkačik, G., &#38; Guet, C. C. (2025). Pulsatile basal gene expression as a fitness determinant in bacteria. <i>Proceedings of the National Academy of Sciences</i>. National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.2413709122\">https://doi.org/10.1073/pnas.2413709122</a>","ista":"Jain K, Hauschild R, Bochkareva O, Römhild R, Tkačik G, Guet CC. 2025. Pulsatile basal gene expression as a fitness determinant in bacteria. Proceedings of the National Academy of Sciences. 122(15), e2413709122."},"volume":122,"day":"15"}]