Uncovering nitroxoline activity spectrum, mode of action and resistance across Gram-negative bacteria
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 demo...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-04-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58730-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849709683126829056 |
|---|---|
| author | Elisabetta Cacace Manuela Tietgen Meike Steinhauer André Mateus Tilman G. Schultze Marina Eckermann Marco Galardini Vallo Varik Alexandra Koumoutsi Jordan J. Parzeller Federico Corona Askarbek Orakov Michael Knopp Amber Brauer-Nikonow Peer Bork Celia V. Romao Michael Zimmermann Peter Cloetens Mikhail M. Savitski Athanasios Typas Stephan Göttig |
| author_facet | Elisabetta Cacace Manuela Tietgen Meike Steinhauer André Mateus Tilman G. Schultze Marina Eckermann Marco Galardini Vallo Varik Alexandra Koumoutsi Jordan J. Parzeller Federico Corona Askarbek Orakov Michael Knopp Amber Brauer-Nikonow Peer Bork Celia V. Romao Michael Zimmermann Peter Cloetens Mikhail M. Savitski Athanasios Typas Stephan Göttig |
| author_sort | Elisabetta Cacace |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-fb10e7a8b3304d74ba0b33c31b44c7cd |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-fb10e7a8b3304d74ba0b33c31b44c7cd2025-08-20T03:15:12ZengNature PortfolioNature Communications2041-17232025-04-0116111610.1038/s41467-025-58730-5Uncovering nitroxoline activity spectrum, mode of action and resistance across Gram-negative bacteriaElisabetta Cacace0Manuela Tietgen1Meike Steinhauer2André Mateus3Tilman G. Schultze4Marina Eckermann5Marco Galardini6Vallo Varik7Alexandra Koumoutsi8Jordan J. Parzeller9Federico Corona10Askarbek Orakov11Michael Knopp12Amber Brauer-Nikonow13Peer Bork14Celia V. Romao15Michael Zimmermann16Peter Cloetens17Mikhail M. Savitski18Athanasios Typas19Stephan Göttig20Goethe University Frankfurt, University Hospital, Institute for Medical Microbiology and Infection ControlGoethe University Frankfurt, University Hospital, Institute for Medical Microbiology and Infection ControlGoethe University Frankfurt, University Hospital, Institute for Medical Microbiology and Infection ControlEuropean Molecular Biology Laboratory, Genome Biology UnitGoethe University Frankfurt, University Hospital, Institute for Medical Microbiology and Infection ControlEuropean Synchrotron Radiation Facility (ESRF)Institute for Molecular Bacteriology, TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI)European Molecular Biology Laboratory, Genome Biology UnitEuropean Molecular Biology Laboratory, Genome Biology UnitGoethe University Frankfurt, University Hospital, Institute for Medical Microbiology and Infection ControlEuropean Molecular Biology Laboratory, Genome Biology UnitEuropean Molecular Biology Laboratory, Structural and Computational Biology UnitEuropean Molecular Biology Laboratory, Genome Biology UnitEuropean Molecular Biology Laboratory, Structural and Computational Biology UnitEuropean Molecular Biology Laboratory, Structural and Computational Biology UnitInstituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de LisboaCluster of Excellence RESIST (EXC 2155), Hannover Medical School (MHH)European Synchrotron Radiation Facility (ESRF)European Molecular Biology Laboratory, Genome Biology UnitEuropean Molecular Biology Laboratory, Genome Biology UnitGoethe University Frankfurt, University Hospital, Institute for Medical Microbiology and Infection ControlAbstract 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.https://doi.org/10.1038/s41467-025-58730-5 |
| spellingShingle | Elisabetta Cacace Manuela Tietgen Meike Steinhauer André Mateus Tilman G. Schultze Marina Eckermann Marco Galardini Vallo Varik Alexandra Koumoutsi Jordan J. Parzeller Federico Corona Askarbek Orakov Michael Knopp Amber Brauer-Nikonow Peer Bork Celia V. Romao Michael Zimmermann Peter Cloetens Mikhail M. Savitski Athanasios Typas Stephan Göttig Uncovering nitroxoline activity spectrum, mode of action and resistance across Gram-negative bacteria Nature Communications |
| title | Uncovering nitroxoline activity spectrum, mode of action and resistance across Gram-negative bacteria |
| title_full | Uncovering nitroxoline activity spectrum, mode of action and resistance across Gram-negative bacteria |
| title_fullStr | Uncovering nitroxoline activity spectrum, mode of action and resistance across Gram-negative bacteria |
| title_full_unstemmed | Uncovering nitroxoline activity spectrum, mode of action and resistance across Gram-negative bacteria |
| title_short | Uncovering nitroxoline activity spectrum, mode of action and resistance across Gram-negative bacteria |
| title_sort | uncovering nitroxoline activity spectrum mode of action and resistance across gram negative bacteria |
| url | https://doi.org/10.1038/s41467-025-58730-5 |
| work_keys_str_mv | AT elisabettacacace uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT manuelatietgen uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT meikesteinhauer uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT andremateus uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT tilmangschultze uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT marinaeckermann uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT marcogalardini uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT vallovarik uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT alexandrakoumoutsi uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT jordanjparzeller uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT federicocorona uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT askarbekorakov uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT michaelknopp uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT amberbrauernikonow uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT peerbork uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT celiavromao uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT michaelzimmermann uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT petercloetens uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT mikhailmsavitski uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT athanasiostypas uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria AT stephangottig uncoveringnitroxolineactivityspectrummodeofactionandresistanceacrossgramnegativebacteria |