A novel group of agents known as the indole-2-carboxamides (often referred to as indoleamides) have been shown to demonstrate high antimycobacterial activity. Studies have demonstrated that the best indoleamides possess desirable ADME/Tox properties, with less adverse effects and increased efficacy against both MDR-TB (multi-drug resistant TB) and XDR-TB (extensively drug-resistant TB). The primary mechanism of killing Mycobacterium tuberculosis (Mtb) by indoleamides is by disrupting the function of the essential mycolic acid transporter MmpL3 protein (Mycobacterial membrane protein Large 3). Therefore, targeting this essential mycobacterial transporter by small molecules opens new possibility for the development of novel and effective anti-TB agents. In the present study, we characterized the effects of indoleamides in altering the viability of Mtb in an in vitro granuloma model using immune cells derived from healthy subjects and those with type 2 diabetes mellitus (T2DM). Our results indicate that treatment with the best indoleamide 3 resulted in a significant reduction in the viability of Mtb in both THP-1 macrophages as well as in granulomas derived from healthy individuals and subjects with T2DM. Graphical Abstract.
Keywords: Cytokines; Drug discovery; Infection immunity; Innate immunity; Intracellular parasitology; Mycobacterium tuberculosis.