Monoterpenoid Geraniol Improves Anti-mycobacterial Drug Efficiency by Interfering with Lipidome and Virulence of Mycobacteria

Background: Tuberculosis (TB) remains a global infectious disorder for which efficient therapeutics are elusive. Nature is a source of novel pharmacologically active compounds with many potential drugs being derived directly or indirectly from plants, microorganisms and marine organisms. Objective: The present study aimed to elucidate the antimycobacterial potential of Geraniol (Ger), monoterpene alcohol, against Mycobacterium smegmatis. Methods: Disrupted membrane integrity was studied by membrane permeability assay and PI uptake. Cell surface phenotypes were studied by colony morphology, sliding motility and cell sedimentation rate. Lipidome profile was demonstrated by thin-layer chromatography and liquid chromatography-electrospray ionization mass spectrometry. Amendment in iron homeostasis was assessed by using iron chelator ferrozine and ferroxidase assay while genotoxicity was estimated with EtBr and DAPI staining. Biofilm formation was measured by staining, dry mass and metabolic activity using crystal violet. Cell adherence was examined microscopically and spectrophotometrically. Results: We found the antimycobacterial activity of Ger to be 500 μg/ml against M. smegmatis. Underlying mechanisms revealed impaired cell surface phenotypes. Lipidomics analysis exposed profound decrement of mycolic acids, phosphatidylinositol mannosides and triacylglycerides which are crucial for MTB pathogenicity. We further explored that Ger impairs iron homeostasis and leads to genotoxic stress. Moreover, Ger inhibited the potential virulence attributes such as biofilm formation and cell adherence to both polystyrene surface and epithelial cells. Finally, we have validated all the disrupted phenotypes by RT-PCR which showed good correlation with the biochemical assays. Conclusion: Taken together, the current study demonstrates the antimycobacterial mechanisms of Ger, which may be exploited as an effective candidate of pharmacological interest.