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This thesis describes the cultivation and extraction of filamentous fungi isolated from extreme environments in the search for new antibiotic compounds. Filamentous fungi are a rich source of medicines including antibiotics, and it is believed that many currently unknown fungal species and bioactive fungal metabolites remain to be discovered. Aspergillus fumigatus and Penicillium nalgiovense strains were isolated from an antibiotic-contaminated riverbed near Hyderabad, India, and soil taken from a penguin’s nest on Paulete Island, Antarctica, respectively. It was anticipated that the extreme conditions within these environments would exert unusual selective pressures on their filamentous fungi, possibly causing the secretion of new bioactive compounds. The cultivation, extraction and analysis of metabolites from the A. fumigatus strain resulted in the isolation of the antimicrobial substance gliotoxin. Subsequent investigations revealed that this strain’s secretion of gliotoxin was increased by as much as 65 % when it was cultivated in the presence of pathogen-associated molecular patterns. These results indicate the existence of a fungal receptor/signaling system for detecting nearby bacteria. The scope for using gliotoxin and the related metabolite bis(methyl)gliotoxin as biomarker metabolites for diagnosing the lethal pulmonary condition invasive aspergillosis was also investigated. Bronchoalveolar lavage fluid from 42 patients with and without possible invasive aspergillosis was extracted and analyzed. The results obtained suggest that gliotoxin and bis(methyl)gliotoxin are not suitable markers for diagnosing invasive aspergillosis. Studies on the P. nalgiovense strain from Antarctica resulted in the isolation of the antifungal agent amphotericin B. The secretion of this compound increased when P. nalgiovense was cultured on a potato-dextrose agar enriched with coconut flakes rather than liquid RPMI 1640 medium. This was the first time amphotericin B was isolated from any organism other than the bacterium Streptomyces nodosus. The results presented in this thesis will be useful in the continuing search for novel bioactive compounds, the diagnosis of fungal infections, and as a source of insight into the interactions between microorganisms. Moreover, they show that even extensively studied fungal genera such as Aspergillus and Penicillium are not completely understood and may produce unexpected or previously unknown bioactive metabolites under appropriate conditions.

Australia's marine environment covers extended areas, from the warm northern tropical, to the sub tropical central water, the cool temperate water of the south and the cold sub-Antarctic and Antarctic water. Australia has rich area of coral reefs. The marine biodiversity in Australia is enormous. Despite incredible biodiversity, Australian research in the marine anticancer drug discoveries is low in comparison with other countries. In this research we investigated a collection of marine sponges as a source for new anticancer leads. This thesis comprises six chapters. Chapter 1 covers the importance of natural products as a source of new drugs, and an introduction to cancer as a disease, chemotherapy in cancer treatments, and the natural products as a source for anticancer drugs. Also, the basic anticancer drug development process is highlighted. Finally, a thorough review of anticancer alkaloids isolated from marine sponges is presented. Chapter 2 presents the chemical investigation into a southern Australian marine sponge Stelletta sp., which led to the isolation and structure elucidation of bistellettazines A-C the first reported examples of terpenyl-pyrrolizidines conjugate, and bistellettazole A, a unique cyclic terpenyl-imidazole conjugate. Bistellettazines A-C and bistellettazole A feature unprecedented carbon skeletons that are proposed to share a common convergent biosynthetic origin, arising via the biogenic equivalent of a Diels-Alder addition between two hypothetical polyenyl norsesquiterpene precursors. The cytotoxic activity (in vitro) for these new alkaloids is also discussed. Chapter 3 discusses the isolation and structure elucidation of four new discorhabdins analogues namely, dihydrodiscorhabdin A, debromodiscorhabdin A, discorhabdin X and dihydrodiscorhabdin L. In addition, the known compounds discorhabdin A and discorhabdin D, were isolated from two southern Australian marine sponge specimens of the genera Higginsia and Spongosorites. The cytotoxic activity (in vitro) for these new alkaloids was also discussed. Chapter 4 discloses chemical investigation into two southern Australian marine sponge specimens of the genera Clathria and Ptilocaulis. Four new mirabilin analogues (mirabilins H-K) were isolated and characterized along with known mirabilin C, F (for the first time as TFA salt) and mirabilin G. The cytotoxic activity (in vitro) for these new alkaloids was also discussed. Chapter 5 presents the 1H NMR data for the known compounds isolated during this study, and Chapter 6 is covering the experimental part.

Australia's marine environment covers extended areas, from the warm northern tropical, to the sub tropical central water, the cool temperate water of the south and the cold sub-Antarctic and Antarctic water. Australia has rich area of coral reefs. The marine biodiversity in Australia is enormous. Despite incredible biodiversity, Australian research in the marine anticancer drug discoveries is low in comparison with other countries. In this research we investigated a collection of marine sponges as a source for new anticancer leads. This thesis comprises six chapters. Chapter 1 covers the importance of natural products as a source of new drugs, and an introduction to cancer as a disease, chemotherapy in cancer treatments, and the natural products as a source for anticancer drugs. Also, the basic anticancer drug development process is highlighted. Finally, a thorough review of anticancer alkaloids isolated from marine sponges is presented. Chapter 2 presents the chemical investigation into a southern Australian marine sponge Stelletta sp., which led to the isolation and structure elucidation of bistellettazines A-C the first reported examples of terpenyl-pyrrolizidines conjugate, and bistellettazole A, a unique cyclic terpenyl-imidazole conjugate. Bistellettazines A-C and bistellettazole A feature unprecedented carbon skeletons that are proposed to share a common convergent biosynthetic origin, arising via the biogenic equivalent of a Diels-Alder addition between two hypothetical polyenyl norsesquiterpene precursors. The cytotoxic activity (in vitro) for these new alkaloids is also discussed. Chapter 3 discusses the isolation and structure elucidation of four new discorhabdins analogues namely, dihydrodiscorhabdin A, debromodiscorhabdin A, discorhabdin X and dihydrodiscorhabdin L. In addition, the known compounds discorhabdin A and discorhabdin D, were isolated from two southern Australian marine sponge specimens of the genera Higginsia and Spongosorites. The cytotoxic activity (in vitro) for these new alkaloids was also discussed. Chapter 4 discloses chemical investigation into two southern Australian marine sponge specimens of the genera Clathria and Ptilocaulis. Four new mirabilin analogues (mirabilins H-K) were isolated and characterized along with known mirabilin C, F (for the first time as TFA salt) and mirabilin G. The cytotoxic activity (in vitro) for these new alkaloids was also discussed. Chapter 5 presents the 1H NMR data for the known compounds isolated during this study, and Chapter 6 is covering the experimental part.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniversitet, 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv. / Härtill 5 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniversitet, 2004. / Härtill 4 uppsatser.

Thesis (PhD) - University of Canberra. / "March 2006" Submitted in accordance with assessment requirements for the Doctor of Philosophy degree of the University of Canberra. Bibliography: p. 228 - 250.