Natural Product Research in TB Drug Discovery

With 16 M active and 9 M new cases, and an estimated 2 M lethal infections per annum, TB is a leading global infectious threat. TB treatment is still difficult, mainly due to multi-drug resistance (MDR). Natural products play an important role in the interdisciplinary approach to TB drug discovery taken at the ITR. In order to generate lead structures, explore drug targets, and evaluate alternative medicine, TB-specific biological and chemical tools are developed as part of an integrated pharmacognostic tactic against the globally rising (MDR-)TB problem. In order to redefine the TB bioassay-guided fractionation process from the biological perspective, new HTS-capable bioassay tools are employed such as luminescence assays using luciferase recombinant H37Rv strains of Mycobacterium tuberculosis, and a reporter gene low oxygen recovery assay (LORA) that mimics TB dormancy conditions in vitro. On the natural product chemistry end, a new biochemometric approach that utilized high-resolution bio-chromatograms has been developed and used to pin down the active principle of anti-TB botanicals. Method development in countercurrent chromatography (CCC) and nuclear magnetic resonance (NMR) technology fosters the chemical characterization of potential drug lead structures, supports the characterization of well-defined natural products mixtures (qNMR) that can be further evaluated in vitro (macrophage assay) and even in vivo (TB infected mice). The interplay of mycobacteriological and chemical methods will be exemplified by experimental proof of anti-TB synergism of natural products and small molecule metabolomics of TB in different growth stages.