AUTHOR=Nitschke Jahn , Huber Robin , Vossio Stefania , Moreau Dimitri , Marcourt Laurence , Gindro Katia , Queiroz Emerson F. , Soldati Thierry , Hanna Nabil 

TITLE=Discovery of anti-infective compounds against Mycobacterium marinum after biotransformation of simple natural stilbenes by a fungal secretome

JOURNAL=Frontiers in Microbiology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1439814

DOI=10.3389/fmicb.2024.1439814

ISSN=1664-302X

ABSTRACT=<sec><title>Introduction</title><p><italic>Mycobacterium tuberculosis</italic> (Mtb), the causative agent of tuberculosis, remains a serious threat to human health worldwide and the quest for new anti-tubercular drugs is an enduring and demanding journey. Natural products (NPs) have played a significant role in advancing drug therapy of infectious diseases.</p></sec><sec><title>Methods</title><p>This study evaluated the suitability of a high-throughput infection system composed of the host amoeba <italic>Dictyostelium discoideum</italic> (Dd) and <italic>Mycobacterium marinum</italic> (Mm), a close relative of Mtb, to identify anti-infective compounds. Growth of Dd and intracellular Mm were quantified by using luminescence and fluorescence readouts in phenotypic assays. The system was first benchmarked with a set of therapeutic anti-Mtb antibiotics and then used to screen a library of biotransformed stilbenes.</p></sec><sec><title>Results</title><p>The study confirmed both efficacy of established antibiotics such as rifampicin and bedaquiline, with activities below defined anti-mycobacterium susceptibility breakpoints, and the lack of activity of pyrazinamide against Mm. The screening revealed the promising anti-infective activities of <italic>trans</italic>-δ-viniferins and in particular of two compounds <bold>17</bold> and <bold>19</bold> with an IC<sub>50</sub> of 18.1 μM, 9 μM, respectively. Both compounds had no activity on Mm in broth. Subsequent exploration via halogenation and structure-activity relationship studies led to the identification of derivatives with improved selectivity and potency. The modes of action of the anti-infective compounds may involve inhibition of mycobacterial virulence factors or boosting of host defense.</p></sec><sec><title>Discussion</title><p>The study highlights the potential of biotransformation and NP-inspired derivatization approaches for drug discovery and underscores the utility of the Dd-Mm infection system in identifying novel anti-infective compounds.</p></sec>