Visualising molecular level detail in single cells and intact tissues. The goal of this project is to deliver a new toolkit for imaging cells at an unprecedented resolution and level of chemical detail. We will expand the capabilities of two existing, but complementary, methods: optical fluorescence microscopy with responsive probes and X-ray fluorescence imaging. Expected outcomes include improved techniques and benchmarks for visualising bacterial and mammalian cells; development of new molecu ....Visualising molecular level detail in single cells and intact tissues. The goal of this project is to deliver a new toolkit for imaging cells at an unprecedented resolution and level of chemical detail. We will expand the capabilities of two existing, but complementary, methods: optical fluorescence microscopy with responsive probes and X-ray fluorescence imaging. Expected outcomes include improved techniques and benchmarks for visualising bacterial and mammalian cells; development of new molecules for elucidating cellular chemistry; better utilisation of valuable synchrotron resources; and greater understanding of the strengths and limitations of current microscopy workflows. Results should benefit the biotechnology sector, and may lead to improved medical, diagnostic, and bioremediation capacity.Read moreRead less
Understanding how cells store and use iron . This project aims to understand the mechanism and function of the protein nanocage, ferritin, which stores iron in the body ready for use on demand. Iron is an essential element, vital for wellbeing. To understand iron we need to understand ferritin. Despite being widely studied, how ferritin actually works remains unclear. This project aims to use an interdisciplinary approach combining protein biochemistry, spectroscopy, genetics and whole organism ....Understanding how cells store and use iron . This project aims to understand the mechanism and function of the protein nanocage, ferritin, which stores iron in the body ready for use on demand. Iron is an essential element, vital for wellbeing. To understand iron we need to understand ferritin. Despite being widely studied, how ferritin actually works remains unclear. This project aims to use an interdisciplinary approach combining protein biochemistry, spectroscopy, genetics and whole organism studies. It will develop new techniques to enable the physiological role of iron to be explored. Outcomes of this innovative platform are anticipated to include in-depth understanding of how ferritin functions to unravel its fundamental role in iron storage and release ready for re-use.Read moreRead less
Mycobacterial Cholesterol Degradation: A Unique Metabolic Weakness? This project aims to understand the use of the steroid cholesterol as a source of essential metabolic building blocks by bacteria. Cholesterol utilisation is a key feature of many bacterial pathogens which have evolved to survive in niche environments. By understanding the initial step in cholesterol degradation and the bioinorganic and bioorganic chemistry of the metalloenzymes that catalyse it, this work aims to develop strate ....Mycobacterial Cholesterol Degradation: A Unique Metabolic Weakness? This project aims to understand the use of the steroid cholesterol as a source of essential metabolic building blocks by bacteria. Cholesterol utilisation is a key feature of many bacterial pathogens which have evolved to survive in niche environments. By understanding the initial step in cholesterol degradation and the bioinorganic and bioorganic chemistry of the metalloenzymes that catalyse it, this work aims to develop strategies to block this activity. This will turn a key strength of these bacteria into a potent weakness and will generate the proof of principle and knowledge required for the future development of effective strategies to combat pathogenic bacteria.Read moreRead less
Discovering New Chemistry and Potential Applications of Metal Tetrapyrroles. This project aims to make fundamental advances in inorganic chemistry, coordination chemistry and bioinorganic chemistry by preparing new metal-containing molecules based on specifically designed tetrapyrrole ligands. Innovative synthetic methods will be developed to enable systematic chemical modifications to explore the chemical and biological properties of the metal complexes. The potential of the new molecules to be ....Discovering New Chemistry and Potential Applications of Metal Tetrapyrroles. This project aims to make fundamental advances in inorganic chemistry, coordination chemistry and bioinorganic chemistry by preparing new metal-containing molecules based on specifically designed tetrapyrrole ligands. Innovative synthetic methods will be developed to enable systematic chemical modifications to explore the chemical and biological properties of the metal complexes. The potential of the new molecules to be of use as tracers for molecular imaging will be investigated. An expected outcome of this research will be an increased understanding of how chemical properties dictate the biological activity of metal complexes informing the potential long-term translation of this chemistry to to new molecular diagnostics and therapeutics.Read moreRead less
Mechanisms maintaining mitochondrial copper homeostasis. This project aims to define the molecular mechanisms by which copper is trafficked and balanced within mitochondria. The project will employ an integrated biological, biochemical, biophysical and structural approach to examine the proteins which underpin the balance between the essentiality for copper and its toxicity, within this organelle. This project will deliver fundamental insights into how mitochondria contribute to and achieve cell ....Mechanisms maintaining mitochondrial copper homeostasis. This project aims to define the molecular mechanisms by which copper is trafficked and balanced within mitochondria. The project will employ an integrated biological, biochemical, biophysical and structural approach to examine the proteins which underpin the balance between the essentiality for copper and its toxicity, within this organelle. This project will deliver fundamental insights into how mitochondria contribute to and achieve cellular metal homeostasis, in addition to molecular explanations for how faults in this process result in mitochondrial defects. Major benefits include research training, strengthened international linkages and fundamental insights into mitochondrial biochemistry.Read moreRead less
Metal Virulence and Therapeutic Factors in Pathogen Bioinorganic Chemistry. The aim is to gain insights into the bioinorganic chemistry that occurs when immune system cells encounter pathogens and the soles of virulence factors and immune system enhancing roles of metal ions. Pathogenic bacteria and fungi accumulate chromium (Cr) in their membranes/outer capsules, which we discovered is likely to be a previously unknown, but important, virulence factor. Hyperaccummulation of nickel (Ni) is also ....Metal Virulence and Therapeutic Factors in Pathogen Bioinorganic Chemistry. The aim is to gain insights into the bioinorganic chemistry that occurs when immune system cells encounter pathogens and the soles of virulence factors and immune system enhancing roles of metal ions. Pathogenic bacteria and fungi accumulate chromium (Cr) in their membranes/outer capsules, which we discovered is likely to be a previously unknown, but important, virulence factor. Hyperaccummulation of nickel (Ni) is also involved in virulence, whereas vanadium (V) enhances the immune system response to these pathogens. Fundamental insights into these roles of Cr, Ni and V will be investigated using advanced spectroscopic, imaging and biochemical techniques. These insights will provide new knowledge on the innate immune system.Read moreRead less
Biologically inert probes to unravel nutrient directed cellular processing . In this project we will develop novel compounds that can act as probes of the pathways present in cells for the uptake of nutrients and other essential molecules and show how to generate new agents for identifying and targeting specific populations of cells. The project will generate new tools for understanding biological processes including cell transport and processing. The insights gained from this work are expected ....Biologically inert probes to unravel nutrient directed cellular processing . In this project we will develop novel compounds that can act as probes of the pathways present in cells for the uptake of nutrients and other essential molecules and show how to generate new agents for identifying and targeting specific populations of cells. The project will generate new tools for understanding biological processes including cell transport and processing. The insights gained from this work are expected to help guide the development of new agents for selectively delivering imaging and biologically active agents to cells.Read moreRead less
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
Bioelectrochemical interconversion of the building blocks of life. This project aims to harness the efficiency of enzymes (Nature’s catalysts) by coupling them with an electrode for the electrochemical interconversion of carbon dioxide, carbon monoxide and formate; the organic building blocks of life. The significance of this research is that the efficient capture and reduction of carbon dioxide is an important quest in the environment and energy sectors. The expected outcomes of this project wi ....Bioelectrochemical interconversion of the building blocks of life. This project aims to harness the efficiency of enzymes (Nature’s catalysts) by coupling them with an electrode for the electrochemical interconversion of carbon dioxide, carbon monoxide and formate; the organic building blocks of life. The significance of this research is that the efficient capture and reduction of carbon dioxide is an important quest in the environment and energy sectors. The expected outcomes of this project will be an understanding of the reactivity of these enzymes and the conditions under which they may be utilised as part of a renewable electrochemical system. Benefits of this research should emerge in energy efficient technologies for generating fuels (formic acid) from waste products (carbon dioxide).Read moreRead less
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