Nitroxoline revisited: antibacterial mechanisms, spectrum, and therapeutic potential of an old drug in the era of antimicrobial resistance.

As the spread of antimicrobial resistance outpaces antibiotic discovery and marketing, there is a critical need to revisit approved compounds with untapped potential. Metal-based complexes (metallo-antimicrobials) represent ideal candidates for such efforts due to their pleiotropic effects, which, unlike antibiotics with single protein targets, may have lower resistance potential. With its well-characterised safety profile, nitroxoline, an 8-hydroxyquinoline derivative, is a prominent compound of this kind. Here, we review recent advances in our understanding of nitroxoline's multimodal mode of action, focusing on its disruption of metal homeostasis at the intracellular and extracellular level. We further explore its clinical utility, including its low propensity for resistance development, and its potential for both combinatorial therapy and as an anti-biofilm agent. Although beyond the scope of the present review, we refer to nitroxoline's antifungal effects whenever they represent a relevant comparison with its antibacterial activity. We highlight current knowledge gaps in nitroxoline's mechanism and in vivo activity that should be bridged to accelerate its repurposing, particularly in the treatment of multidrug-resistant and biofilm-associated infections. Several recent reviews have examined nitroxoline from chemical, clinical, and repurposing perspectives [1, 2, 3, 4]. The present work complements these by providing a mechanistic synthesis of nitroxoline's effects in bacteria, linking its multimodal mode of action to the knowledge gaps that should be addressed before clinical repurposing can proceed.