Biology subjects

Fries, F.

Publications and source records attributed to Fries, F..

3 recordsLinked to original sources

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↗

bioRxiv2026

Structure Elucidation, Biosynthesis and Biological Evaluation of Neosorangicin A, a Member of the Sorangicin Family

Antimicrobial resistance represents an escalating global health crisis, with drug-resistant infections predicted to cause up to 10 million deaths annually by 2050, underscoring the urgent need for novel antibiotics. Natural products play a crucial role in the discovery and development of antibiotics, with myxobacteria emerging as a particularly promising source due to their ability to produce structurally diverse and bioactive compounds. One prominent example of antibiotics from myxobacteria are the sorangicins, potent inhibitors of the bacterial RNA polymerase (RNAP). Here, we report the isolation of two unprecedented compounds, neosorangicin A (1) and neosorangioside A (2), from Sorangium cellulosum strain Soce439, elucidated their molecular structures, thereby revealing significant structural variation in comparison to sorangicin, and describe their biosynthetic pathway. Neosorangicin A (1) exhibited strong activity against various Gram-positive bacteria, with enhanced potency on intracellular Staphylococcus aureus. In a murine wound infection model, a head-to-head comparison of neosorangicin A (1) and sorangicin A (3) provided useful insights into how the altered physicochemical properties, arising from the shortened side chain and the lack of the free carboxylic acid of neosorangicin A, influence the in vivo efficacy of sorangicin derivatives.

microbiology↗

bioRxiv2024

Cystobactamid off-target profiling reveals favorable safety, superoxide reduction, and SCARB1 inhibition in eukaryotes

Antimicrobial resistance (AMR) poses a fundamental global threat, necessitating new strategies for effective therapies. Cystobactamids (CYS), a class of antibacterial agents targeting bacterial gyrase and topoisomerase IV, represent a non-traditional chemical scaffold with broad-spectrum activity. For toxicological de-risking, we performed a comprehensive profiling on eukaryotic cells, focusing on cytotoxicity, genotoxicity, and mitochondrial toxicity, demonstrating cellular safety and superoxide scavenging properties. Studies in zebrafish embryos assessed developmental, cardiovascular, and hepatic toxicity, indicating a favorable in vivo safety profile. Metabolism studies revealed glucuronidation and amide bond hydrolysis as key pathways, whereby CYS metabolic stability substantially improved by cobicistat co-treatment. Affinity-based protein profiling identified the cholesterol- and HCV-receptor scavenger receptor class B member 1 (SCARB1) as a primary eukaryotic off-target protein, with cystobactamids shown to inhibit SCARB1s function, preventing hepatitis C virus pseudoparticle entry into cells. These findings suggest a high therapeutic potential for cystobactamids and highlight SCARB1 as a primary eukaryotic target.

pharmacology and toxicology↗