New methods for structure analysis of proteins and protein interactions. This project will advance nuclear magnetic resonance (NMR) technologies pioneered at the Australian National University which employ site-specific attachment of paramagnetic metal tags to proteins. A new and diverse set of strategies will dramatically extend the range of applications to targets of interest in the fight against cancer and bacterial infections.
Structure function analysis of the NusA-RNA polymerase interaction. Genes must be turned on at the right time, at the correct level in the appropriate cell in all organisms. This project will determine the role of an essential component of the process in bacteria called NusA. The results will apply to bacteria as well as higher organisms, and also have the potential to identify a new antibiotic target.
Unraveling autotransporter function in bacterial aggregates and biofilms. Autotransporters are a large family of bacterial proteins that play a central role in pathogenesis. They promote the formation of cell clusters and biofilms, which are mechanisms for bacterial resistance to host immune factors and antibiotics. Currently, the precise mode of action of autotransporters is unknown. This project will examine the interplay between the structure and function of key autotransporter proteins. It ....Unraveling autotransporter function in bacterial aggregates and biofilms. Autotransporters are a large family of bacterial proteins that play a central role in pathogenesis. They promote the formation of cell clusters and biofilms, which are mechanisms for bacterial resistance to host immune factors and antibiotics. Currently, the precise mode of action of autotransporters is unknown. This project will examine the interplay between the structure and function of key autotransporter proteins. It is expected that the outcomes of this research will establish how these proteins mediate aggregation and biofilm formation. It may also provide three-dimensional structures of proteins that are strongly immunogenic and may represent targets for future vaccine design, as well as identify molecules that inhibit autotransporter function.Read moreRead less
Mathematical models of diseases with complex transmission routes. This project aims to model diseases that spread via a mixture of routes including food, water, the environment, and direct spread between individuals. Key diseases include: avian influenza, which causes massive disruption to the poultry industry; gastroenteritis, which costs Australia $1,250 million each year; and leptospirosis, which causes one million severe illnesses each year globally. This project will develop mathematical a ....Mathematical models of diseases with complex transmission routes. This project aims to model diseases that spread via a mixture of routes including food, water, the environment, and direct spread between individuals. Key diseases include: avian influenza, which causes massive disruption to the poultry industry; gastroenteritis, which costs Australia $1,250 million each year; and leptospirosis, which causes one million severe illnesses each year globally. This project will develop mathematical and statistical tools to better estimate risk, analyse outbreak data, and provide guidance for disease control. This research will improve policy and enhance our ability to respond to disease outbreaks.Read moreRead less
Drug discovery and structural biology by NMR spectroscopy. This project aims to extend the use of nuclear magnetic resonance (NMR) spectroscopy in rational drug development and protein structure analysis. A new chemical labelling approach provides detailed three-dimensional structure information of large protein-ligand complexes, needed for structure-based lead-compound development. New chemical and paramagnetic lanthanide tags for site-specific dual labelling of proteins will enhance this techn ....Drug discovery and structural biology by NMR spectroscopy. This project aims to extend the use of nuclear magnetic resonance (NMR) spectroscopy in rational drug development and protein structure analysis. A new chemical labelling approach provides detailed three-dimensional structure information of large protein-ligand complexes, needed for structure-based lead-compound development. New chemical and paramagnetic lanthanide tags for site-specific dual labelling of proteins will enhance this technology, which will assess target-drug interactions by in-cell electron paramagnetic resonance (EPR) spectroscopy. The techniques offer scope for accelerated drug development in the pharmaceutical industries.Read moreRead less
New methods for structural biology and drug discovery by nuclear magnetic resonance spectroscopy. Paramagnetic lanthanide tags offer fresh opportunities in structural biology and for rational drug design. Novel nuclear magnetic resonance (NMR) spectroscopy techniques will selectively detect the NMR signals from protein regions marked by paramagnetic lanthanides, accelerating the structure analysis of protein-ligand complexes. New lanthanide tags will bind to phosphoserine and selenocysteine resi ....New methods for structural biology and drug discovery by nuclear magnetic resonance spectroscopy. Paramagnetic lanthanide tags offer fresh opportunities in structural biology and for rational drug design. Novel nuclear magnetic resonance (NMR) spectroscopy techniques will selectively detect the NMR signals from protein regions marked by paramagnetic lanthanides, accelerating the structure analysis of protein-ligand complexes. New lanthanide tags will bind to phosphoserine and selenocysteine residues site-specifically introduced into proteins. These tags will also enable accurate distance measurements by electron paramagnetic resonance (EPR) spectroscopy in large, biologically important protein systems hitherto not amenable to detailed structural studies and in proteins undergoing conformational changes. Read moreRead less
Multiscale models in immuno-epidemiology. The spread of a pathogen (for example, a virus or bacteria) through a population is a multi-scale phenomena, influenced by factors acting at both the population and within-host scales. At the population scale, transmission is influenced by how infectious an infected host is. Infectiousness in turn depends on the balance between pathogen replication within the host and immune/drug control mechanisms. This project aims to develop new mathematical framework ....Multiscale models in immuno-epidemiology. The spread of a pathogen (for example, a virus or bacteria) through a population is a multi-scale phenomena, influenced by factors acting at both the population and within-host scales. At the population scale, transmission is influenced by how infectious an infected host is. Infectiousness in turn depends on the balance between pathogen replication within the host and immune/drug control mechanisms. This project aims to develop new mathematical frameworks for simultaneously modelling these two scales. This will provide a platform for the rigorous study of complex biological interactions - such as the emergence and combat of drug-resistance - that shape society's ability to control infectious diseases in human, animal and plant systems.Read moreRead less
Molecular Interactions with an antibiotic target in DNA replication. This project aims to develop and use new technologies to address mechanistic aspects of anti-bacterial compounds in development, and of the development of resistance to them. The project will focus on the sliding clamp subunit of the bacterial replicative polymerase by studying its association with many other proteins in vitro and in vivo, using novel techniques in solid-state NMR, single-molecule fluorescence and molecular mic ....Molecular Interactions with an antibiotic target in DNA replication. This project aims to develop and use new technologies to address mechanistic aspects of anti-bacterial compounds in development, and of the development of resistance to them. The project will focus on the sliding clamp subunit of the bacterial replicative polymerase by studying its association with many other proteins in vitro and in vivo, using novel techniques in solid-state NMR, single-molecule fluorescence and molecular microbiology. The outcomes are expected to be an increased understanding of bacterial DNA replication and mechanisms of antibiotic action and resistance. This project expects to generate new knowledge to assist in combatting antibiotic resistance in Gram-negative bacterial pathogens.Read moreRead less
New methods for integrating population structure and stochasticity into models of disease dynamics. Epidemics, such as the 2007 equine 'flu outbreak and 2009 swine 'flu pandemic, highlight the need to make informed decisive responses. This project will develop new methods that incorporate two important aspects of disease dynamics---host structure and chance---into mathematical models, and determine their impact in terms of controlling infections.
How auto-transporter proteins mediate bacterial interactions. This project aims to investigate the structure-function relationships that underpin key auto-transporter roles in bacterial cell adhesion, aggregation and biofilm formation. Auto-transporter proteins are extremely common in bacteria where they play a central role in controlling bacterial interactions with other bacteria, with human cells, and with surfaces. This project will define the molecular mechanisms underlying these processes. ....How auto-transporter proteins mediate bacterial interactions. This project aims to investigate the structure-function relationships that underpin key auto-transporter roles in bacterial cell adhesion, aggregation and biofilm formation. Auto-transporter proteins are extremely common in bacteria where they play a central role in controlling bacterial interactions with other bacteria, with human cells, and with surfaces. This project will define the molecular mechanisms underlying these processes. This will have significant benefits, such as providing the basis for the development of approaches to block auto-transporter functions that contribute to the establishment of persistent and difficult to treat bacterial infections.Read moreRead less