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 | Research Interests |  |
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| General Description of Our Work: Marine Natural Products Chemistry |
| | Biodiscovery or bioprospecting is the multi disciplinary search for and evaluation of naturally occurring bioactive molecules. Drug discovery, production and sales is a world-wide multi billion dollar industry that impacts at all levels of modern life. From the antibiotics that treat infections, to the analgesics that relieve pain, to drug treatments for such specific ailments as hay fever, cancer, blood pressure and arthritis, through anti parasitic agents that control fly, tick and nematode infestations in commercial livestock and the family pet, to the antifungal and insecticidal products that protect crops both pre and post harvest our quality of life is dependent on continued access to safe and effective drugs. Much of the existing repertoire of drugs are either natural products, or were derived from bioactive natural products. Bioprospecting can make significant contributions to basic and applied science, education and training, as well as regional and national economic development.
As important scientific breakthroughs reveal more about the molecular nature of disease, unravelling genetic associations, and drawing attention to key molecular targets, far from being diminished, the need to explore unique pools of biodiversity is more profound than ever. Biodiversity collections encapsulate libraries of unparalleled molecular variety and complexity. The myriad of molecular motifs encountered in even a modest collection of several thousand microbial extracts far exceeds the capacity of even the largest research program to synthesise. This is not to imply that our ability to synthesise target molecules is not without value, on the contrary it is critical to success. Rather, this observation serves to highlight the pivotal role that bioprospecting plays in discovering leads. Once discovered these leads become the inspiration for exploring the pharmacophore, ultimately leading to the discovery of new pharmaceuticals, agrochemicals, and molecular probes.
The Centre for Molecular Biodiversity seeks to advance and focus the role of Australian biodiversity (marine and terrestrial - plants, algae, invertebrates and microbes) in drug discovery. CMB Biodiversity Libraries are subjected to chemical, spectroscopic and biological profiling in order to detect potent new drug candidates. In close collaboration with industry partners, these substances are isolated, identified and assessed for possible application in the fields of human and animal health, and crop protection.
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| New antibiotics from Australian terrestrial microbes. |
| | Antibiotics underpin much of modern health care, and the threat to this form of therapy by multiple drug resistance pathogens is real and immediate. Combating drug resistance poses a significant cost to the health budget, with failure leading to suffering and tragic loss of life. Although the vast majority of existing antibiotics originate from microbial cultures, Australian microbes are poorly explored in this regard. A library of Australian microbes (>200,000) established by Microbial Screening Technologies is known to include strains with promising antibiotic characteristics. This project supports exploration of this resource to discover new antibiotics effective against drug resistant pathogens. |
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| Non-toxic inhibitors of cell adhesion from Australian marine algae. |
| | Selective toxicity has been a fundamental tenet of drug discovery, whether it be the search for substances to combat cancer, microbes or parasitesÉ afflicting humans, animals or crops. Therapeutic value is typically a measure of relative toxicity to host versus disease, with extreme toxicity to the host being an all too necessary compromise. This project will discover non toxic drugs that target the relationship between disease and host at a cellular level. Australian algae uniquely free of epiphytes will be screened for their ability to inhibit cell adhesion, and the isolated active agents evaluated as pharmaceuticals, agrochemicals, and antifouling agents.
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| Anticancer agents from Australian marine biodiversity. |
| | World-wide it is estimated that in 2003 some 8.1 million people will be diagnosed with cancer, of which 5.2 million will die. Excluding non-melanocytic skin cancers (NMSC), the Australian statistics for 1999 revealed >82,000 new cancer cases, with 35,000 deaths. In that same year 270,000 Australians were diagnosed with NMSC. Cancers currently account for 29% of Australian male deaths and 25% of Australian female deaths, with almost one third of all Australians who died in 2001 having a malignant cancer. Anticancer drugs are a critical weapon in the fight against cancer. Many of these drugs possess exquisite and complex molecular structures that engage and interact with important biomolecules. Historically the discovery of such molecules has drawn heavily on bioactive natural products. Particularly noteworthy, in recent years we have glimpsed the extraordinary untapped potential of marine biodiversity as a source of next generation anticancer drugs.
This project aims to explore Australian marine biodiversity as a means to discover new and improved anticancer drug candidates. It further seeks to develop these drug candidates into commercially acceptable therapeutics, with the capacity to manage and treat cancers, and contribute to global health care. |
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| Australian marine metabolites as agrochemicals. |
| | The ever increasing world population presents an enormous challenge to existing agricultural infrastructure and practices. With ~10% of the worldÕs land surface under agriculture there is little scope for expansion. Agricultural experts estimate that world-wide more that one third of crop yield is lost to insect pests, diseases and weeds, in the fields, and during storage and transport. To put these losses into perspective they are equivalent to the total annual agricultural output of the USA. Furthermore, without the use of crop protection products (fungicides, insecticides, herbicides...) it is estimated that world-wide yields would drop by a further 30-60% and be subject to significant fluctuations. Similar figures apply to agricultural livestock production which is dependent on the efficient use of crop protection strategies in the growing of feed, and in the application of animal health products (anthelmintics, antibiotics...) to ensure healthy and productive livestock. The quest for new and improved agrochemicals, with highly selective modes of action capable of targeting specific pests and diseases, draws heavily on natural products chemistry.
This project aims to explore Australian marine biodiversity as a source of bioactive metabolites with potential application as agrochemicals. Such agrochemicals will act by new molecular modes of action and as such be effective against pests and diseases that are resistant to current commercial agrochemicals. Such outcomes offer the potential for significant environmental and economic returns to the nation.
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| Marine Microbial Biodiscovery: Environmentally Sustainable Drug Discovery |
| | Microbial biodiversity has been a fundamental resource in the discovery of modern pharmaceuticals, including such therapeutics as antibacterials (penicillins, tetracyclins, cephalosporins, aminoglycosides), antifungals (nystatins), antiparasitics (avermectins), anticancer (anthracyclins, glycopeptides), immunosuppressant (cyclosporin A), or cholesterol lowering agents (mevastatin, lovastatin). In the area of antimicrobials alone, four of the leading products, Augmentin¨, Zithromax¨, Biaxin¨ and Rocephin¨, are microbial in origin with annual sales > US$1 billion. Despite impressive successes over the last 50-100 years, the quest for new drugs continues as diseases relentlessly evolve and share resistance to existing pharmaceuticals, and as we seek to develop safer and more effective treatments for an ever wider range of human illness.
Past successes with microbial biodiversity might suggest that the discovery of next generation drugs requires merely a continuation of past discovery practices. After all, microbes have almost limitless biodiversity, produce a remarkable array of structurally complex bioactive metabolites, and industrial scale fermentation provides ready market access to quality pharmaceuticals at affordable prices. Where we once found good drugs from microbes surely we can find more. Unfortunately the reality of drug discovery is more challenging. While microbes continue to be the preferred source for drug discovery, for all the reasons outlined above, we need to be more innovative in how and more importantly where we search for new and improved drugs.
As the pharmaceutical industry explores overlapping microbial biodiversity libraries they are confronted by reduced molecular novelty and the added burden and cost in dollars and time of rediscovering prior work. The challenge posed by dereplication cannot be underestimated, as it reduces discovery rates, increases costs and in extreme cases influences pharmaceutical companies to abandon biodiscovery altogether. A key strategy to minimizing the impact of replication, and to reinvigorating the role of microbes in drug discovery, is to target unique and unexplored pools of microbial biodiversity. Unexplored biodiversity equates to unexplored molecular diversity, leading to new bioactive molecular motifs with improved scope for drug discovery. An easy enough concept, but after 100 years exploration by the pharmaceutical industry one might reasonably ask ÒÉwhere on Earth will we find new microbial biodiversity?Ó Curiously the answer is not to be found on Earth so much as in the Oceans. Marine ecosystems dominate the planet and host biodiversity at least equal to, and by some estimates far in excess of that found on land. This project seeks to access Australian marine microbial biodiversity as a resource for drug discovery.
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