Fungi have been an inspiring source of diverse secondary metabolites, with a number of metabolites developed as pharmaceuticals and agrochemicals. Despite the past success, fungal biodiscovery has been challenged with the excessive rediscovery of known metabolites. This thesis is focused on investigating four selected strategies to explore fungal secondary metabolite potential to discover novel and bioactive metabolites. This includes, bioactivity-guided isolation, varying cultivation conditions, application of advance analytical techniques and microbial co-cultivation. A library of ×185 microbes, including fungi (×132) and Streptomyces (×53), was constructed from a total of ×28 samples collected from terrestrial and marine samples. High-throughput miniaturized 24-well microbioreactor culture approach was used to generate extracts from solid (agar) and liquid (broth shaken) cultures to prepare a crude extract library, which was subjected to chemical and bioactivity profiling using HPLC-DAD-MS and UHPLC-QTOF. Two innovative bioassays to discover bioactive metabolites in the extracts were employed; (i) The larval development assay (LDA), used to detect anti-parasitic metabolites against drug (monepantel) resistant sheep intestinal parasite Haemonchus contortus and (ii) GABA (β-aminobutyric acid) receptor inhibitory activity, to detect molecules that may have application as anti-anxiety drugs. Selected strains were subjected to a program of analytical miniaturized cultivation, supported by UHPLC-DAD-MS and UHPLC-QTOF profiling to explore the wider secondary metabolite potential of fungi. The metabolite production was visualised using the Global Natural Product Social (GNPS) molecular networking analysis. Based on the chemical and bioactivity profiling, a total of ×6 fungi were selected for further investigation, and the isolation and characterization of metabolites from these strains are discussed in this PhD thesis.Chapter 1 highlights the importance of understanding, and exploring silent fungal secondary metabolism. This chapter also reviews different strategies reported in the literature for the discovery of novel and bioactive metabolites from fungi, with main focus on (i) bioactivity guided isolation, (ii) varying cultivation condition, (iii) application of advance analytical techniques and (iv) microbial cocultivation.Chapter 2 focuses on investigating bioactivity-guided isolation as a prioritizing tool for microbial extracts to isolate biologically active metabolites. Anthelmintic metabolites identified from Penicillium sp. CMB-TS015 and Purpureocillium sp. CMB-F551 are discussed in this chapter.Chapter 3 discusses continued chemical and bioactivity investigation on Penicillium sp. CMB-TS015.Isolation, characterization and bioactivity profiling of three new fungal metabolites (+)spiroquinazoline B, (+)-fumiquinazoline J and the tetramic acid chaunolidine D, are described in this chapter.
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