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

Rapport Preprint Discovery of anti-infective compounds against Mycobacterium marinum after biotransformation of simple natural stilbene scaffolds by a fungal secretome eng 2024-04-22 author Nitschke Jahn 0000-0003-3838-0945 919314 author Huber Robin 402520 author Vossio Stefania 666435 Département de biochimie (CHIBI) author Moreau Dimitri 0000-0002-9282-3324 751508 Plateforme ACCESS (ACCESS) author Marcourt Laurence 729234 Section des sciences pharmaceutiques (FARMA) author Gindro Katia author Ferreira Queiroz Emerson 135675 Section des sciences pharmaceutiques (FARMA) author Soldati Thierry 0000-0002-2056-7931 135632 Département de biochimie (CHIBI) author Hanna Nabil 0000-0002-3288-5486 856070 Département de biochimie (CHIBI) 10.1101/2024.04.18.590143 http://biorxiv.org/lookup/doi/10.1101/2024.04.18.590143 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. Dewey 540 39 Département de biochimie 144 false 766 Groupe Soldati ef645126-f29d-4ab7-8ed4-08121ca3542c Preprint Public Nitschke_et_al_2024.pdf 6608206 application/pdf b392a9a5234c8c628cc1a0fe9236175bdebc93b90c0202c2e6b18caeaa7663e6 openAccess Faculté des sciences / Section de chimie et biochimie / Département de biochimie

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Discovery of anti-infective compounds against Mycobacterium marinum after biotransformation of simple natural stilbene scaffolds by a fungal secretome				2024	17	92

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Huber, Robin