Walzer, N. | Search bioRxiv

bioRxiv2026

Pathogen-driven reactivation of metabolite prodrugs defines nitroxoline's iron-deprivation antibiotic activity

The rise of antimicrobial resistance warrants renewed attention to established but overlooked antibiotics such as nitroxoline (NTX). Here, we systematically dissect NTXs mode of action and investigate the contribution of its first-pass metabolites, NTX-sulphate and NTX-glucuronide. We identified metallophore-mediated cellular iron deprivation as the principal antibacterial mechanism of NTX, characterized by induction of iron acquisition pathways and Fe-S cluster proteins, and concomitant loss of protein-bound iron. In contrast, NTX metabolites were biologically inactive and lacked metal-chelating properties. Ex vivo assays demonstrated that clinically relevant uropathogens, including Escherichia coli and Klebsiella pneumoniae, efficiently reconvert these metabolites into active NTX in human urine. Together, our findings establish a mechanistic framework linking NTX antibacterial activity, host detoxification, and pathogen-dependent metabolite reactivation, and providing a molecular explanation for NTXs enduring therapeutic potential and favourable safety profile.

microbiology↗

bioRxiv2023

The direction of local adaptation on pathogen exploitation rates reverses with environmental context

Host heterogeneity and spatial population structure each influence parasite evolution but may also interact because space structures contacts between host types. Here, we experimentally evolve granulosis virus in microcosms of its Plodia interpunctella (Indian meal moth) host that differ in both spatial structure and host genetic diversity. We control spatial structure by manipulating the viscosity of the food that the larvae live within and host genetic diversity by adding larvae from either a single or two inbred lines to opposite ends of the microcosm. We preserve spatial structure across passages and assay virus from different positions within the microcosm on both host genotypes. We find that the lower contact rates between host genotypes resulting from spatial structure can lead to the evolution of locally specialized virus, even when the host population is genetically diverse overall. We also find that spatial structure changes how viruses specialize: viruses evolved in well-mixed environments had lower exploitation of familiar hosts, while those in spatially structured environments exhibited higher exploitation of familiar hosts. These results demonstrate that spatial structure and host heterogeneity interact to shape pathogen specialization and that the evolutionary consequences of host diversity depends on the population structure.

evolutionary biology↗