Cacace Elisabetta, Tietgen Manuela, Steinhauer Meike, Mateus André, Schultze Tilman G, Eckermann Marina, Galardini Marco, Varik Vallo, Koumoutsi Alexandra, Parzeller Jordan J, Corona Federico, Orakov Askarbek, Knopp Michael, Brauer-Nikonow Amber, Bork Peer, Romao Celia V, Zimmermann Michael, Cloetens Peter, Savitski Mikhail M, Typas Athanasios, Göttig Stephan
Goethe University Frankfurt, University Hospital, Institute for Medical Microbiology and Infection Control, Frankfurt, Germany.
European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
Nat Commun. 2025 Apr 22;16(1):3783. doi: 10.1038/s41467-025-58730-5.
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.
硝羟喹啉是一种具有抑菌作用的喹啉类抗生素，已知可与金属形成复合物。其临床适应症仅限于单纯性尿路感染，且仅对大肠杆菌有药敏折点。在此，我们测试了1000多种临床分离株，证明其具有更广泛的活性谱和种属特异性杀菌活性，包括因多重耐药而治疗选择有限的革兰氏阴性菌。通过将基因和蛋白质组学方法与细胞内金属的直接测量相结合，我们表明硝羟喹啉作为一种金属载体，可诱导细菌细胞内铜和锌中毒。该化合物对细菌生理学还有其他影响，包括外膜完整性的改变，这是硝羟喹啉与大型支架抗生素协同作用以及在体外和体内使耐黏菌素肠杆菌科细菌重新敏感的基础。此外，我们确定了不同细菌物种间保守的耐药机制，这些机制通常导致硝羟喹啉外排。
