Uncovering nitroxoline activity spectrum, mode of action and resistance across Gram-negative bacteria
Cacace E, Tietgen M, Steinhauer M, Mateus A, Schultze T, Eckermann M, Galardini M, Varik V, Koumoutsi A, Parzeller J, Corona F, Orakov A, Knopp M, Brauer-Nikonow A, Bork P, Romao C, Zimmermann M, Cloetens P, Savitski M, Typas A, Göttig S
Published in
Nature Communications: Volume 16, Issue 1, Page 3783
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.
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