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 -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, 17 with an IC ₅₀ of 18.1 µM, and 19 with an IC ₅₀ of 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.

IMPORTANCE

This 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 -δ-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.