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

Authors:
Open Access
Publisher website
Google Scholar
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.
All Related Versions
Funding Information
  • Marie Skłodowska-Curie Actions COFUND
  • Deutsche Forschungsgemeinschaft (390874280)
  • Bundesministerium für Forschung, Technologie und Raumfahrt (LAMarCK, 031L0181A)
  • Vetenskapsrådet (2019-00666)
  • Paul G. Allen Frontiers Group

This publication has 101 references indexed in Scilit: