Structural Characterisation Of A Natural Inhibitor Of Sporulation Bound To Its Histidine Kinase Target
Funder
National Health and Medical Research Council
Funding Amount
$261,000.00
Summary
Many bacteria, including some which are virulent pathogens such as anthrax (Bacillus anthracis), are able to enter a dormant state by forming spores (sporulation). These spores are extremely robust and may persist in the environment buried in the soil for example for hundreds of years. The initiation of sporulation occurs in response to changes in the cellular and environmental conditions which threaten the free replicating existence of the bacterium. The process of sporulation is controlled at ....Many bacteria, including some which are virulent pathogens such as anthrax (Bacillus anthracis), are able to enter a dormant state by forming spores (sporulation). These spores are extremely robust and may persist in the environment buried in the soil for example for hundreds of years. The initiation of sporulation occurs in response to changes in the cellular and environmental conditions which threaten the free replicating existence of the bacterium. The process of sporulation is controlled at the molecular level by a complex signaling relay. It is of course vital for the existence of the organism that control of sporulation is tightly regulated - preventing the onset of spore-formation in any but the desired circumstances. We aim to determine the three-dimensional structures of the molecules involved in this regulated process and how, by interacting with each other, they can pass on the signal to the bacterium to either start or stop the spore forming process. Ultimately, the results of this work might lead to antibacterial agents which could be used to control particularly dangerous strains of bacteria.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE120102263
Funder
Australian Research Council
Funding Amount
$375,000.00
Summary
Export of effector proteins by P. falciparum to the infected red blood cell. Infection by the malaria parasite has lethal consequences for humans. The parasite exports hundreds of proteins via a translocon to commandeer the red blood cell. This project aims to determine the function of one of the major translocon components and determine if it is a viable target for anti-malarial drug development.
Molecular basis of the antifungal and antimalarial activity of a plant defensin. The plant defensin NaD1 has potent inhibitory activity against a number of agronomically important fungal pathogens. These species are major pathogens of cotton and other important agricultural crops such as canola and potatoes. These pathogens cause serious economic losses and threaten the future of the cotton industry in Australia. NaD1 also has potential as a new antibiotic for treatment of infections in human ....Molecular basis of the antifungal and antimalarial activity of a plant defensin. The plant defensin NaD1 has potent inhibitory activity against a number of agronomically important fungal pathogens. These species are major pathogens of cotton and other important agricultural crops such as canola and potatoes. These pathogens cause serious economic losses and threaten the future of the cotton industry in Australia. NaD1 also has potential as a new antibiotic for treatment of infections in humans.Read moreRead less
Cells must regulate the flow of ions and water across their membranes in order to survive and function normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first to identify and characterise a new class of chloride channel wh ....Cells must regulate the flow of ions and water across their membranes in order to survive and function normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first to identify and characterise a new class of chloride channel which plays a key roles in the regulation of the immune system. These channels are unusual in that they can move between two states: a soluble state and a state that resides in the cell membrane. We have determined the first structures of this class of channel in both the soluble state and what is believed to be the membrane docking state. This has given us the first atomic picture of how this channel protein can alter its structure so as to carry out its function. In this project, we will determine: how the protein completes the transition into the membrane state; the structures of other key members of this class of channel protein; complexes between channel proteins and other cellular proteins; and the structure of the protein in the membrane state. We will also determine how several drugs control the activity of this channel. The results of our work will have specific implications for our channel and will serve as a paradigm other members of this new class of chloride channel. Understanding how this channel functions and how the current drugs control it will lead to the development of a new class of therapeutic agents that will control these channels by preventing the transition from the soluble to the membrane state.Read moreRead less
Ion transport in the malaria parasite and parasitised erythrocyte. This work will contribute to the national research effort in parasitology (an area in which the ARC has established a Research Network), as well as laying the groundwork for subsequent efforts (not part of this grant) to develop new antimalarial strategies. Although not yet endemic in Australia, malaria is a serious problem in the local region and, as the major developed nation in the region Australia has an obligation to make ....Ion transport in the malaria parasite and parasitised erythrocyte. This work will contribute to the national research effort in parasitology (an area in which the ARC has established a Research Network), as well as laying the groundwork for subsequent efforts (not part of this grant) to develop new antimalarial strategies. Although not yet endemic in Australia, malaria is a serious problem in the local region and, as the major developed nation in the region Australia has an obligation to make a significant contribution to research in this area. The work proposed here will contribute to Australia's meeting this obligation.Read moreRead less
Amino acid transporters and the chloroquine resistance transporter of the intracellular malaria parasite. This work entails an ongoing collaboration between three independent research groups with highly complementary expertise and experience. It will make a significant contribution to the maintenance of Australia's scientific capabilities and training opportunities. The project will yield important insights into the biology of the causative agent of a major human disease, and the mechanism by ....Amino acid transporters and the chloroquine resistance transporter of the intracellular malaria parasite. This work entails an ongoing collaboration between three independent research groups with highly complementary expertise and experience. It will make a significant contribution to the maintenance of Australia's scientific capabilities and training opportunities. The project will yield important insights into the biology of the causative agent of a major human disease, and the mechanism by which the malaria parasite has developed resistance to antimalarial drugs. Although not yet endemic in Australia, malaria is a serious problem in the local region and this work will help Australia meet its obligations to carry out high-quality research that advances our knowledge in this area.
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Functional proteomics of Giardia. This project will use the latest tools for dissecting and comparing genes and their protein products from one of the most common parasites infecting people, their pets, livestock and wildlife. This protozoan parasite Giardia is also of evolutionary and biological significance in terms of understanding the origin of higher animals from bacteria as well as fundamental questions about the parasitic way of life. Giardia proteins will be identified and characterised ....Functional proteomics of Giardia. This project will use the latest tools for dissecting and comparing genes and their protein products from one of the most common parasites infecting people, their pets, livestock and wildlife. This protozoan parasite Giardia is also of evolutionary and biological significance in terms of understanding the origin of higher animals from bacteria as well as fundamental questions about the parasitic way of life. Giardia proteins will be identified and characterised on the basis of their value in understanding disease processes and treatment, and by working with appropriate industry partners, proteins of commercial value will be exploited.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE170100575
Funder
Australian Research Council
Funding Amount
$372,000.00
Summary
Pathogen detection in mammals. This project aims to study the role of a host molecule in immune protection. Multicellular organisms need to recognise pathogens to initiate immune protection. To do this, pathogen-specific molecules are presented to the immune system causing activation. Recently a mode of pathogen recognition was discovered in mammals. As microbes synthesise essential vitamins, they release tell-tale metabolite by-products, which a host molecule called MR1 captures and presents to ....Pathogen detection in mammals. This project aims to study the role of a host molecule in immune protection. Multicellular organisms need to recognise pathogens to initiate immune protection. To do this, pathogen-specific molecules are presented to the immune system causing activation. Recently a mode of pathogen recognition was discovered in mammals. As microbes synthesise essential vitamins, they release tell-tale metabolite by-products, which a host molecule called MR1 captures and presents to white blood cells. However, it is not understood how MR1 accomplishes this, the cellular machinery required, or how the metabolites are guided to MR1. Understanding this process is expected to explain microbial pathogen recognition.Read moreRead less
A mechanism for pathogen detection highly conserved in mammals. This project aims to delineate biochemically how mammals fight pathogens by alerting their immune system to Vitamin B compounds produced by certain bacteria and fungi. The protein MR1 binds the compounds and displays them on the cell surface, activating pathogen-fighting MAIT cells. The MR1-MAIT cell axis is highly conserved in mammals and is thought to defend the host. This project expects to lead to new products to improve veterin ....A mechanism for pathogen detection highly conserved in mammals. This project aims to delineate biochemically how mammals fight pathogens by alerting their immune system to Vitamin B compounds produced by certain bacteria and fungi. The protein MR1 binds the compounds and displays them on the cell surface, activating pathogen-fighting MAIT cells. The MR1-MAIT cell axis is highly conserved in mammals and is thought to defend the host. This project expects to lead to new products to improve veterinary and human health services with new technology developed throughout the project and high-level training which will increase the competitiveness of the strategic biotechnology sector in Australia.Read moreRead less