Discovery of anti-infective compounds againstMycobacterium marinumafter biotransformation of simple natural stilbene scaffolds by a fungal secretome

Abstract

ABSTRACTThis study evaluated the efficacy of a high-throughputDictyostelium discoideum–Mycobacterium marinumDd-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 intracellularMycobacterium 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-δ-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,17with an IC50of 18.1 µM, and19with an IC50of 9 µM). 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-throughputDictyostelium discoideum-Mycobacterium marinuminfection system on a small, focused library of natural product derivatives, the study identifiedtrans-δ-viniferins as promising anti-infective scaffolds againstMycobacterium 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.