Queiroz, E. F. | bioRxiv Science

bioRxiv2026

Human airway organoids as a high-throughput screening platform for antiviral natural products discovery

Antiviral drug discovery for respiratory viruses is hindered by the lack of scalable physiologically relevant systems. Here, we report the first high-throughput screen of 764 natural plant extracts against respiratory syncytial virus (RSV) using human primary airway organoids as a relevant model. A parallel screen conducted in A549 cells allowed the identification of 70 extracts with organoid-specific antiviral activity from which 45 active phytocompounds were purified. We identified early- and late-acting antiviral compounds and demonstrated a polarization-dependent activity for some of them. Collectively, our results establish the use of airway organoids as a scalable first-line platform for high-throughput antiviral discovery and exploit the plant-derived chemical space as an underexplored source of RSV inhibitors.

microbiology↗

bioRxiv2024

Discovery of anti-infective compounds against Mycobacterium marinum after biotransformation of simple natural stilbene scaffolds by a fungal secretome

This study evaluated the efficacy of a high-throughput Dictyostelium discoideum - Mycobacterium marinum Dd-Mm infection system by first benchmarking it against a set of antibiotics and second in screening a library of natural product (NP) derivatives for anti-infective activity against intracellular Mycobacterium marinum (Mm). The study observed no activity of pyrazinamide against Mm, consistent with known resistance patterns, and confirmed other antibiotics, such as rifampicin and bedaquiline, with activity below defined antibacterial susceptibility breakpoints. From screening a small library of NP derivatives, trans-{delta}-viniferins emerged as promising anti-infective scaffolds, particularly two compounds which exhibited an anti-infective activity on Mm during infection but not on Mm in broth, 17 with an IC50 of 18.1 {micro}M, and 19 with an IC50 of 9 {micro}M). Subsequent exploration via halogenation and structure-activity relationship (SAR) studies led to the identification of derivatives with improved selectivity and potency. The observed anti-infective phenotype may involve mechanisms such as blocking mycobacterial virulence factors or boosting host defense. Furthermore, the study highlights the potential of natural product-inspired derivatization approaches for drug discovery and underscores the utility of the Dd-Mm infection system in identifying novel anti-infective compounds. IMPORTANCEThis study underscores the significance of leveraging natural product-inspired approaches and innovative infection models in search for novel anti-infective compounds. By benchmarking and employing high-throughput Dictyostelium discoideum-Mycobacterium marinum infection system on a small, focused library of natural product derivatives, the study identified trans-{delta}-viniferins as promising anti-infective scaffolds against Mycobacterium marinum, opening potential therapeutic avenues for combating tuberculosis. The findings highlight the value of exploring nature-inspired chemistry for drug discovery and addressing global health challenges.

microbiology↗