|Institution:||University of New South Wales|
|Keywords:||polyketide; antimicrobial; endophytes; traditional medicine; tuberculosis; non-ribosomal peptide|
|Full text PDF:||http://handle.unsw.edu.au/1959.4/55757|
The rapid emergence of antibiotic-resistant pathogens has driven the discovery of new drug leads from natural sources. Traditional medicinal plants have long been investigated as sources of bioactive molecules due to their rich ethnobotanical history. The vast biodiversity and empirical medicinal history of Indonesia make their flora an attractive target for the discovery of novel therapeutic compounds. A large proportion of bioactive natural products are non-ribosomal peptides and polyketides. Many of these compounds, which were originally isolated from plants, have since been found to be produced by their microbial endophytes. It is also understood that the genes encoding the biosynthesis of these bioactive molecules are useful for dereplication. Therefore, genetic and bioactivity screening of culturable endophytes from twelve traditional Indonesian medicinal plants used to treat symptoms of tuberculosis was conducted to identify strains capable of producing potential antitubercular polyketides and peptides. Phylogenetic analysis of the endophytes revealed a rich community of bacteria from the phyla Firmicutes, Actinobacteria, and Proteobacteria, and fungi from the phylum Ascomycota. A high proportion of these endophytes (83% of bacteria and 94% of fungi) contained either non-ribosomal peptide or polyketide biosynthetic genes. Preliminary antibacterial screening of the fungi against Gram-positive, Gram-negative, and mycobacterial strains showed most isolates exhibited antiproliferative activity against at least one of the test strains, and suggested a correlation between the biosynthetic genes and bioactivity. Two isolates which exhibited bactericidal activity against M. tuberculosis were selected for active compound isolation. Bioassay- and NMR-guided fractionation resulted in the discovery of four anti-M. tuberculosis polyketides: javanicin and anhydrofusarubin from Fusarium sp. 9RF2 (MIC of 25 μg mL-1 and 50 μg mL-1, respectively), and acropyrone and compound 11UF1.S-5D6B from Endothia sp. 11UF1 (MIC of 50 μg mL-1 and 100 μg mL-1, respectively). This investigation confirmed the hypothesis that traditional medicinal plants are valuable sources of endophytes that produce bioactive compounds. As the world continues to search for novel pharmaceuticals, prospecting of genetic resources, as described in this thesis, is a viable and productive approach that has the potential to be adapted in the context of exploiting traditional medicinal plants from around the world. Advisors/Committee Members: Neilan, Brett, UNSW.