INTRODUCTION

(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 (Dd) and (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 -δ-viniferins and in particular of two compounds and with an IC 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 NP-inspired derivatization approaches for drug discovery and underscores the utility of the Dd-Mm infection system in identifying novel anti-infective compounds.