Chemical genetic analyses of compounds derived from feijoa fruit
Nature has been a rich source of pharmaceutical compounds, producing 80% of our currently prescribed drugs. The feijoa plant, Acca sellowiana, is classified in the family Myrtaceae, native to South America, and currently grown worldwide to produce feijoa fruit. Compounds with anticancer, anti-inflammatory, antibacterial and antifungal activities have been isolated from feijoa; however, the diversity of these compounds is not known nor is the mechanism of action of any of these compounds. I hypothesized that identifying compounds in novel feijoa cultivars would improve our understanding of the chemical diversity of antifungal compounds in feijoa and determining the antifungal mechanism of action of feijoa compounds would provide insight into the pharmaceutical potential of these compounds. First, GC-MS analyses were used to obtain an unbiased profile of 151 compounds from 16 cultivars of feijoa, of which six were novel cultivars. Multivariate analysis distinguished 18 compounds that were significantly and positively correlated to antifungal activity based on growth inhibition of Saccharomyces cerevisiae, of which seven had not previously been described from feijoa. Two novel cultivars were identified as the most bioactive cultivars, and the compound 4-cyclopentene-1,3-dione found in a couple of cultivars was potently antifungal against human pathogenic isolates of four Candida species. Second, chemical genetic analyses were used to investigate the mechanism of action of estragole, an antifungal compound previously isolated from feijoa. The chemical genetic profile of estragole was distinct from that of other known antifungal compounds, suggesting the mechanism of action of estragole has a novel antifungal mechanism. Third, chemical genetic analyses were used to investigate the mechanism of action of an ethanol adduct of vescalagin (EtOH-vescalagin) isolated from feijoa. We showed EtOH-vescalagin is antifungal against human pathogenic strains. Genome-wide chemical genetic analyses of EtOH-vescalagin indicated antifungal activity is mediated by disruptions of iron homeostasis, zinc homeostasis and retromer recycling through iron chelation. Overall, these results indicate the chemical and biological value of feijoa as a source of antifungal drugs.