Introduction: Mycobacterium tuberculosis (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.
Methods: This study evaluated the suitability of a high-throughput infection
system composed of the host amoeba Dictyostelium discoideum (Dd) and
Mycobacterium marinum (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.
Results: 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 trans-δ-
viniferins and in particular of two compounds 17 and 19 with an IC50 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.
Discussion: The study highlights the potential of biotransformation and NPinspired
derivatization approaches for drug discovery and underscores the utility
of the Dd-Mm infection system in identifying novel anti-infective compounds.
