Chemical Genetic Analyses of Kānuka ('Kunzea ericoides') Extracts

Nature is enriched with a diverse range of chemical entities that have  therapeutic value. Traditional medicine is based on these compounds, with medicinal plants providing some of modern medicines most important pharmaceuticals. New Zealand is unique for its endemic native flora, but most have yet to be heavily investigated for pharmaceutical potential.  One such plant is Kunzea ericoides (kānuka). Traditional Māori medicine indicates it has similar uses to that of mānuka, yet its bioactivity and pharmaceutical potential is unknown. In this thesis, the mechanisms of kānuka leaf extracts were explored using chemical genetics. One extract,  S2-15, was found to be highly potent out of six different extracts. A genome-wide analysis using the haploid deletion mutant library of the genetic model Saccharomyces cerevisiae (Baker’s yeast) revealed deletion of the sirtuin SIR2 gene (sir2∆) was particularly resistant to S2-15  treatment demonstrating 20% increased growth when compared to the untreated control. When further investigated, the chronological lifespan of sir2∆ was not significantly reduced when treated with S2-15. However, the chronological lifespan of the target of rapamycin gene deletion (tor1∆) was completely reduced by S2-15 at day 3 compared to the untreated control. These results lead to an experiment that  demonstrated growth inhibition of yeast was synergistic with dual treatment of S2-15 and rapamycin. A new batch of kānuka extracts revealed 30KG to be the most potent out of four different extracts. Via a proteomic screen of a GFP-tagged library of yeast strains, the process of lipid metabolism was identified as a mechanism of 30KG treatment. Further analysis showed that 30KG abolished lipid droplet number in WT cells, and also reduced the size and number of lipid droplets in the obese mutant tgl3∆tgl4∆ that is deficient in breaking down triglycerides. Together, these results demonstrate that kānuka extracts exhibit bioactivity involved in chronological ageing and lipid metabolism that can be utilized for pharmaceutical potential.