IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58730-5.html
   My bibliography  Save this article

Uncovering nitroxoline activity spectrum, mode of action and resistance across Gram-negative bacteria

Author

Listed:
  • Elisabetta Cacace

    (Institute for Medical Microbiology and Infection Control
    Genome Biology Unit)

  • Manuela Tietgen

    (Institute for Medical Microbiology and Infection Control)

  • Meike Steinhauer

    (Institute for Medical Microbiology and Infection Control)

  • André Mateus

    (Genome Biology Unit)

  • Tilman G. Schultze

    (Institute for Medical Microbiology and Infection Control)

  • Marina Eckermann

    (European Synchrotron Radiation Facility (ESRF)
    University of Bern)

  • Marco Galardini

    (a joint venture between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI)
    Hannover Medical School (MHH))

  • Vallo Varik

    (Genome Biology Unit)

  • Alexandra Koumoutsi

    (Genome Biology Unit)

  • Jordan J. Parzeller

    (Institute for Medical Microbiology and Infection Control)

  • Federico Corona

    (Genome Biology Unit)

  • Askarbek Orakov

    (Structural and Computational Biology Unit)

  • Michael Knopp

    (Genome Biology Unit)

  • Amber Brauer-Nikonow

    (Structural and Computational Biology Unit)

  • Peer Bork

    (Structural and Computational Biology Unit)

  • Celia V. Romao

    (Universidade Nova de Lisboa)

  • Michael Zimmermann

    (Hannover Medical School (MHH))

  • Peter Cloetens

    (European Synchrotron Radiation Facility (ESRF))

  • Mikhail M. Savitski

    (Genome Biology Unit)

  • Athanasios Typas

    (Genome Biology Unit)

  • Stephan Göttig

    (Institute for Medical Microbiology and Infection Control)

Abstract

Nitroxoline is a bacteriostatic quinoline antibiotic, known to form complexes with metals. Its clinical indications are limited to uncomplicated urinary tract infections, with a susceptibility breakpoint only available for Escherichia coli. Here, we test > 1000 clinical isolates and demonstrate a much broader activity spectrum and species-specific bactericidal activity, including Gram-negative bacteria for which therapeutic options are limited due to multidrug resistance. By combining genetic and proteomic approaches with direct measurement of intracellular metals, we show that nitroxoline acts as a metallophore, inducing copper and zinc intoxication in bacterial cells. The compound displays additional effects on bacterial physiology, including alteration of outer membrane integrity, which underpins nitroxoline’s synergies with large-scaffold antibiotics and resensitization of colistin-resistant Enterobacteriaceae in vitro and in vivo. Furthermore, we identify conserved resistance mechanisms across bacterial species, often leading to nitroxoline efflux.

Suggested Citation

  • Elisabetta Cacace & Manuela Tietgen & Meike Steinhauer & André Mateus & Tilman G. Schultze & Marina Eckermann & Marco Galardini & Vallo Varik & Alexandra Koumoutsi & Jordan J. Parzeller & Federico Cor, 2025. "Uncovering nitroxoline activity spectrum, mode of action and resistance across Gram-negative bacteria," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58730-5
    DOI: 10.1038/s41467-025-58730-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58730-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-58730-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Nils Kurzawa & Isabelle Becher & Sindhuja Sridharan & Holger Franken & André Mateus & Simon Anders & Marcus Bantscheff & Wolfgang Huber & Mikhail M. Savitski, 2020. "A computational method for detection of ligand-binding proteins from dose range thermal proteome profiles," Nature Communications, Nature, vol. 11(1), pages 1-8, December.
    2. Iskander Khusainov & Natalie Romanov & Camille Goemans & Beata Turoňová & Christian E. Zimmerli & Sonja Welsch & Julian D. Langer & Athanasios Typas & Martin Beck, 2024. "Bactericidal effect of tetracycline in E. coli strain ED1a may be associated with ribosome dysfunction," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. André Mateus & Johannes Hevler & Jacob Bobonis & Nils Kurzawa & Malay Shah & Karin Mitosch & Camille V. Goemans & Dominic Helm & Frank Stein & Athanasios Typas & Mikhail M. Savitski, 2020. "The functional proteome landscape of Escherichia coli," Nature, Nature, vol. 588(7838), pages 473-478, December.
    4. Seung-Hwan Choi & Kang-Lok Lee & Jung-Ho Shin & Yoo-Bok Cho & Sun-Shin Cha & Jung-Hye Roe, 2017. "Zinc-dependent regulation of zinc import and export genes by Zur," Nature Communications, Nature, vol. 8(1), pages 1-11, August.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Dezerae Cox & Ching-Seng Ang & Nadinath B. Nillegoda & Gavin E. Reid & Danny M. Hatters, 2022. "Hidden information on protein function in censuses of proteome foldedness," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Marta Ukleja & Lara Kricks & Gabriel Torrens & Ilaria Peschiera & Ines Rodrigues-Lopes & Marcin Krupka & Julia García-Fernández & Roberto Melero & Rosa Campo & Ana Eulalio & André Mateus & María López, 2024. "Flotillin-mediated stabilization of unfolded proteins in bacterial membrane microdomains," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    3. Sandhya Malla & Kanchan Kumari & Carlos A. García-Prieto & Jonatan Caroli & Anna Nordin & Trinh T. T. Phan & Devi Prasad Bhattarai & Carlos Martinez-Gamero & Eshagh Dorafshan & Stephanie Stransky & Da, 2024. "The scaffolding function of LSD1 controls DNA methylation in mouse ESCs," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    4. Cristina Sayago & Jana Sánchez-Wandelmer & Fernando García & Begoña Hurtado & Vanesa Lafarga & Patricia Prieto & Eduardo Zarzuela & Pilar Ximénez-Embún & Sagrario Ortega & Diego Megías & Oscar Fernánd, 2023. "Decoding protein methylation function with thermal stability analysis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Florian P. Bayer & Manuel Gander & Bernhard Kuster & Matthew The, 2023. "CurveCurator: a recalibrated F-statistic to assess, classify, and explore significance of dose–response curves," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    6. Teresa Gil-Gil & Brandon A. Berryhill & Joshua A. Manuel & Andrew P. Smith & Ingrid C. McCall & Fernando Baquero & Bruce R. Levin, 2024. "The evolution of heteroresistance via small colony variants in Escherichia coli following long term exposure to bacteriostatic antibiotics," Nature Communications, Nature, vol. 15(1), pages 1-9, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58730-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.