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

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 and Stephan Göttig ()
Additional contact information
Elisabetta Cacace: Institute for Medical Microbiology and Infection Control
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)
Marco Galardini: a joint venture between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI)
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

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58730-5

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