Tuberculosis (TB) is as a major global threat mostly due to infection with antibiotic resistant forms of Mycobacterium tuberculosis, the causal agent of the disease [1]. The resulting accelerated quest for new anti-mycobacterial agents, has produced targets but with significant toxicity or physical and chemical problems. Given this many are re-examining natural products for their structural, functional and stereochemical diversity that provide unique scaffolds for further drug optimisation. To aid such efforts the targets for natural products should be defined as an essential step for the development of an anti-tubercular drug [2] .
We report the isolation of a compound from hops (Humulus lupulus) with significant in vitro anti-mycobacterial activity (10 µg/mL). Whole-genome sequencing of compound-resistant mutants of M. smegmatis identified a major target. Non-targeted metabolomic by flow infusion ionisation electrospray high-resolution mass spectrometry (FIE-HRMS), lipidomic analysis and in silico studies were employed to independently validate the putative target and obtain valuable insights into the mode of action of this antibiotic. This novel use of FIE-HRMS [3] also permitted the characterisation of metabolic differences between mycobacteria treated with several known antibiotics (first and second line against tuberculosis) and controls. Specific metabolic patterns to pathways leading to cell arrest were defined for our compound that were discrete from any known antibacterial mechanisms. This established the importance of a metabolomic strategy in drug target discovery that could be more widely applied. Beyond this, our definition of a novel target will enable the optimisation or de novo synthesis of new anti-tubercular drugs, avoiding the resistance problems linked to known targets.
[1] WHO. 2016 Global tuberculosis report. [ 2] Baptista R, et al. Future Med Chem. 2018. [ 3] Baptista R, et al. Sci Rep. 2018.