Mixing the jigsaw pieces of natural products: new molecules-new properties. This project aims to examine the capacity of exploiting the bacterial biosynthetic machinery to fast-track access to analogues of natural products. Due to increased drug resistance, new reservoirs of natural products are needed for evaluation as future drugs. Desferrioxamine B will be used as a model natural product to establish the biosynthesis of new analogues in bacterial culture supplemented with unsaturated, fluorin ....Mixing the jigsaw pieces of natural products: new molecules-new properties. This project aims to examine the capacity of exploiting the bacterial biosynthetic machinery to fast-track access to analogues of natural products. Due to increased drug resistance, new reservoirs of natural products are needed for evaluation as future drugs. Desferrioxamine B will be used as a model natural product to establish the biosynthesis of new analogues in bacterial culture supplemented with unsaturated, fluorinated or deuterated building blocks. The intended outcomes are to deliver advances in methods for generating structurally diverse pools of natural products, new label-free probes, knowledge of natural product biosynthesis, and excellence in training research students in frontier methods in chemical biology and drug discovery.Read moreRead less
Resurrecting Ancient Proteins to Unlock New Catalytic Activity. This project aims to study the proteins that nature uses to make penicillin and related antibiotics, and their prehistoric ancestors. By doing so, the project expects to deepen understanding of these important processes, open up ways to make new antibiotics, and generate new knowledge about protein evolution. Intended outcomes include new biocatalysts based on the ancient ones, new antibiotic compounds active against resistant bacte ....Resurrecting Ancient Proteins to Unlock New Catalytic Activity. This project aims to study the proteins that nature uses to make penicillin and related antibiotics, and their prehistoric ancestors. By doing so, the project expects to deepen understanding of these important processes, open up ways to make new antibiotics, and generate new knowledge about protein evolution. Intended outcomes include new biocatalysts based on the ancient ones, new antibiotic compounds active against resistant bacteria, and a richer understanding of how these proteins have evolved over the last 4 billion years. This promises significant benefits in the form of new ways to address the challenge posed by antimicrobial resistance to antibiotics, which is a serious threat to the continued effectiveness of current antibiotics.Read moreRead less
Expanding access to modified proteins via a novel semi-synthetic platform. This project aims to address a critical knowledge gap in understanding how post-translational modifications modulate the structure and activity of proteins. By developing an innovative semi-synthetic platform to produce pure proteins inaccessible by existing methods, the project will reveal how natural protein modifications influence structure and function. Expected outcomes include the delivery of breakthrough technologi ....Expanding access to modified proteins via a novel semi-synthetic platform. This project aims to address a critical knowledge gap in understanding how post-translational modifications modulate the structure and activity of proteins. By developing an innovative semi-synthetic platform to produce pure proteins inaccessible by existing methods, the project will reveal how natural protein modifications influence structure and function. Expected outcomes include the delivery of breakthrough technologies for accessing modified proteins for a range of applications in academia and industry, as well as the generation of new knowledge in the fields of chemistry and biology. The project will lead to the training of interdisciplinary early career researchers and has the potential to benefit Australia’s biotechnology sector.Read moreRead less
CRISPR-based pathway activation for bioactive molecule discovery in fungi. Fungi produce an incredible array of unique bioactive molecules, many of which have contributed greatly to humanity (e.g. the antibiotic penicillin, which has saved millions of lives since its discovery). DNA sequencing has revealed many fungi contain the genetic instructions to produce new molecules that have not been seen previously. However, these genes are “switched off" by default and cannot be accessed. This project ....CRISPR-based pathway activation for bioactive molecule discovery in fungi. Fungi produce an incredible array of unique bioactive molecules, many of which have contributed greatly to humanity (e.g. the antibiotic penicillin, which has saved millions of lives since its discovery). DNA sequencing has revealed many fungi contain the genetic instructions to produce new molecules that have not been seen previously. However, these genes are “switched off" by default and cannot be accessed. This project will develop innovative new methods to "hot-wire" these genes, allowing them to turn on and produce a treasure trove of new bioactive molecules. The outcomes of this project will transform our abilities to tap into the hidden potential of fungi to generate new lead molecules for the agricultural and medical industries.Read moreRead less
Characterisation of the beneficial vs toxic forms of selenium in the diet. This project aims to examine how dietary selenium is converted into essential proteins and beneficial compounds that mitigate against a broad range of human diseases; or alternatively, into toxic molecules. Cutting-edge methodologies should resolve significant unknowns in selenium metabolism, to provide definitive dietary guidelines and to explore how selenium can treat and protect against disease. Expected outcomes from ....Characterisation of the beneficial vs toxic forms of selenium in the diet. This project aims to examine how dietary selenium is converted into essential proteins and beneficial compounds that mitigate against a broad range of human diseases; or alternatively, into toxic molecules. Cutting-edge methodologies should resolve significant unknowns in selenium metabolism, to provide definitive dietary guidelines and to explore how selenium can treat and protect against disease. Expected outcomes from this national and international collaboration include expert training for young biochemical researchers and refinements to novel analytical techniques. Results should benefit the food and agricultural sectors to provide tailored products locally and for export, as well as enhanced health opportunities for all Australians.Read moreRead less
Chemical staples and chemical probes to dissect dynamins cellular roles. Modulation of protein structure drives cellular function. Dynamin GTPase forms at least two macromolecular structures with different cellular functions. The drivers behind these different structures is unknown. In this project we will leverage our discoveries, and planned enhancements, of chemical biology probes that will modulate dynamin activity by inhibiting at three distinct sites, and one site that stimulates dynamin a ....Chemical staples and chemical probes to dissect dynamins cellular roles. Modulation of protein structure drives cellular function. Dynamin GTPase forms at least two macromolecular structures with different cellular functions. The drivers behind these different structures is unknown. In this project we will leverage our discoveries, and planned enhancements, of chemical biology probes that will modulate dynamin activity by inhibiting at three distinct sites, and one site that stimulates dynamin activity. It is known that Dynamin helices and rings are believed responsible for at least three in cell biological functions: in hormone, neutral and receptor internalisation; cellular mitosis and in actin dynamics. Prior to this work we have lacked the tools to understand the role of shape modulation of protein function.Read moreRead less
Micro-dissection of clathrins role in mitosis via chemical biology probes. This project aims to contribute to understanding the molecular mechanisms of the role of a key protein, clathrin, in cell division. In doing so it expects to reveal new approaches to stop uncontrolled cell division and proliferation, the hallmarks of cancer. The outcomes could in the long term inform breakthroughs in cancer treatment, significant enhancements in life quality and a reduction in cancer death rates.
Enzyme-Mediated Machining of Chelators to Bind and Recover Valuable Metals. Metals are critical components of electronic devices and electrical products. Rapid disposal cycles create a major problem in managing e-waste metals and identifies an opportunity in the circular economy for recovery and re-use. Organic compounds that bind metal ions (chelators) are useful but could be improved to select a target metal from a mixture. This project aims to dissect a method used by bacteria to biosynthesiz ....Enzyme-Mediated Machining of Chelators to Bind and Recover Valuable Metals. Metals are critical components of electronic devices and electrical products. Rapid disposal cycles create a major problem in managing e-waste metals and identifies an opportunity in the circular economy for recovery and re-use. Organic compounds that bind metal ions (chelators) are useful but could be improved to select a target metal from a mixture. This project aims to dissect a method used by bacteria to biosynthesize chelators and hijack this to bioengineer new classes of chelators. Outcomes include new chelators and advanced knowledge of metal selectivity, with potential environmental and economic benefits arising from recovery of valuable metals. The project will benefit chemical biology research training for real-world applications.Read moreRead less