Uncovering nitroxoline activity spectrum, mode of action and resistance across Gram-negative bacteria
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.
Authors
- Célia V. Romão (ORCID: https://orcid.org/0000-0002-9474-2405)
- Mikhail M. Savitski (ORCID: https://orcid.org/0000-0003-2011-9247)
- Vallo Varik (ORCID: https://orcid.org/0000-0001-6900-6986)
- Askarbek Orakov (ORCID: https://orcid.org/0000-0001-6823-5269)
- Manuela Tietgen (ORCID: https://orcid.org/0000-0001-5117-4340)
- Federico Corona (ORCID: https://orcid.org/0000-0002-0743-5520)
- Peter Cloetens (ORCID: https://orcid.org/0000-0002-4129-9091)
- Michael Zimmermann (ORCID: https://orcid.org/0000-0002-5797-3589)
- Marco Galardini (ORCID: https://orcid.org/0000-0003-2018-8242)
- Athanasios Typas (ORCID: https://orcid.org/0000-0002-0797-9018)
- Tilman Schultze (ORCID: https://orcid.org/0000-0003-4827-0993)
- Amber Brauer-Nikonow (ORCID: https://orcid.org/0000-0003-4146-2458)
- Elisabetta Cacace (ORCID: https://orcid.org/0000-0001-8239-0353)
- Stephan Göttig (ORCID: https://orcid.org/0000-0001-6896-5309)
- Alexandra Koumoutsi (ORCID: https://orcid.org/0000-0001-8368-4193)
- Peer Bork (ORCID: https://orcid.org/0000-0002-2627-833X)
- Michael Knopp (ORCID: https://orcid.org/0000-0002-8218-3263)
- Marina Eckermann (ORCID: https://orcid.org/0000-0001-6418-4310)
- André Mateus (ORCID: https://orcid.org/0000-0001-8807-4079)
- Jordan J. Parzeller
- Meike Steinhauer
Institutions
- Goethe University Frankfurt (DE)
- University of Bern (CH)
- European Synchrotron Radiation Facility (FR)
- Medizinische Hochschule Hannover (DE)
- Helmholtz Centre for Infection Research (DE)
- University Hospital Frankfurt (DE)
- European Molecular Biology Laboratory (DE)
- Center for Experimental and Clinical Infection Research (DE)
- European Molecular Biology Laboratory (DE)
- Universidade Nova de Lisboa (PT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-22
- DOI
- https://doi.org/10.1038/s41467-025-58730-5
- Citations
- 8
- Primary Topic
- Antibiotic Resistance in Bacteria
- Type
- article
- Field-Weighted Citation Impact
- 4.73
Funders
- Paul G. Allen Frontiers Group
- Deutsche Forschungsgemeinschaft
- European Synchrotron Radiation Facility
- Bundesministerium für Bildung und Forschung
- Vetenskapsrådet
- H2020 Marie Skłodowska-Curie Actions