Anti-mycobacterial natural products from Canadian medicinal plants

Abstract

The global epidemic of tuberculosis (TB) persists in large part due to the development of resistance against current therapies. One potential source for novel anti-TB drugs is natural products. Plants and the natural products that they produce have long been recognized for their medicinal value and are extensively used as traditional medicines, and therefore they represent an important source of anti-mycobacterial natural products. The objective of this thesis was to investigate anti-mycobacterial natural products from Canadian medicinal plants. Four plants that have been used to treat TB, Aralia nudicaulis, Alnus incana, Empetrum nigrum and Moneses uniflora, were selected after preliminary anti-mycobacterial screening of 13 Canadian medicinal plants. A total of 21 natural products were isolated through bioassay guided fractionation of the four plants. Aralia nudicaulis was selected for the exploration of its endophytic community and the C17 diynes isolated from A. nudicaulis were investigated to identify their anti-mycobacterial modes of action. As it has been demonstrated that some endophytes can produce natural products originally attributed to their host, we considered it worthwhile investigating whether the C17 diynes isolated from A. nudicaulis were biosynthesized from the plant de novo or whether they were produced by endophytes. As such, 88 endophytic fungi were isolated from rhizomes of A. nudicaulis and were screened for their ability to produce falcarinol and panaxydol. Unfortunately, neither of the C17 diynes could be detected in the endophytes from our screening. Microarray analysis was used to determine the transcript responses of Mycobacterium smegmatis when treated with the C17 diynes, falcarinol and panaxydol. Principal component analysis suggested a different mode of action of the C17 diynes when compared with commonly used anti-mycobacterial drugs. Functional enrichment and pathway enrichment analysis revealed that there were gene ontologies and pathways preferentially affected by the C17 diynes treatments. The theoretical bioactivities of the two C17 diynes were estimated through prediction of activity spectra of substances (PASS). Based upon these analyses, it is hypothesized that the C17 diynes inhibit fatty acid biosynthesis, specifically phospholipid synthesis, in mycobacteria.