Acetohydroxyacid Synthase: A New Drug Target For Human Fungal Pathogens
Funder
National Health and Medical Research Council
Funding Amount
$536,914.00
Summary
The aim is to discover new compounds that have the ability to reduce the growth of invasive human fungal pathogens including Candida albicans, Cryptococcus neoformans and Aspergillus nidulans. These infectious agents are highly prevalent in hospital patients that are immuno-compromised. The compounds have a common feature in that they prevent the synthesis of valine, leucine and isoleucine which are key metabolites required for the survival of these fungi in the human host.
New Strategies To Target Multiple Drug Resistance In Clinically Relevant Fungal Infections.
Funder
National Health and Medical Research Council
Funding Amount
$378,925.00
Summary
The emergence of multiple drug resistance (MDR) in the community and hospitals is considered a major threat to public health. Fungal bloodstream infections with opportunistic Candida species are of particular concern. Azoles are the most widely used class of antifungals in clinical use, but their efficacy is severely limited by the development of MDR. This project will employ a comprehensive, cross-disciplinary approach to develop novel small-molecule therapeutics for combatting fungal MDR.
Novel Insights Into The Molecular Mechanisms Of Manganese Recognition And Acquisition By Pathogenic Bacteria.
Funder
National Health and Medical Research Council
Funding Amount
$843,035.00
Summary
Streptococcus pneumoniae is the world’s foremost bacterial pathogen. In Australia, bacterial infections are responsible for more than 9000 deaths every year, and the economic burden associated with treating diseases arising from pneumococcal infections is more than $4 billion annually. This proposal aims to define the molecular basis of how bacteria scavenge manganese from the host environment. This knowledge will provide the foundation for next generation antimicrobial therapeutics.
Understanding the mechanisms of ion conduction and drug action in voltage gated sodium channels. Voltage-gated sodium channels initiate electrical impulses in nerve and muscle and are the target of many local anaesthetic, anti-epileptic and anti-arrythmic drugs. The publication of atomic resolution structures of homologous proteins from bacteria in the last 18 months has now made it possible to gain a detailed understanding of how these channels work, and how they are influenced by drugs. This p ....Understanding the mechanisms of ion conduction and drug action in voltage gated sodium channels. Voltage-gated sodium channels initiate electrical impulses in nerve and muscle and are the target of many local anaesthetic, anti-epileptic and anti-arrythmic drugs. The publication of atomic resolution structures of homologous proteins from bacteria in the last 18 months has now made it possible to gain a detailed understanding of how these channels work, and how they are influenced by drugs. This project aims to determine the basis of ion permeation and selectivity in the channels and explain the mechanisms of action for a number of common drugs. This will provide a foundation for future drug development to target specific channels for improved treatment of epilepsy, chronic pain and arrythmias. Read moreRead less
Structural studies of host-pathogen interactions. The host-pathogen interface represents a major frontier for biomedical and biotechnological applications. This project aims to understand at the atomic level two such interfaces. In the first instance, the project will elucidate the molecular basis for inhibition of premature host cell death by poxviruses, in particular vaccinia and variola virus, the causative agent of smallpox. In the second instance, the aim is to understand how defensins, a ....Structural studies of host-pathogen interactions. The host-pathogen interface represents a major frontier for biomedical and biotechnological applications. This project aims to understand at the atomic level two such interfaces. In the first instance, the project will elucidate the molecular basis for inhibition of premature host cell death by poxviruses, in particular vaccinia and variola virus, the causative agent of smallpox. In the second instance, the aim is to understand how defensins, a major class of host defence molecules, recognise microbial targets such as fungi, and exert a potent antimicrobial effect. Understanding the precise molecular mechanisms operating at both these host-pathogen interfaces this will provide novel avenues for the design of antiviral and antimicrobial agents.Read moreRead less
Hydrophobin proteins on the fungal frontline. This project aims to use advanced biophysical techniques to study the role of hydrophobin proteins in three diseases caused by fungi. The specific focus will be on hydrophobins from fungal species that cause severe loss of rice plants, cause invasive growths in humans, and infect the eggs of endangered turtles and result in death of the turtle embryos. Hydrophobins are small fungal proteins that assemble into large biological layers at the boundary ....Hydrophobin proteins on the fungal frontline. This project aims to use advanced biophysical techniques to study the role of hydrophobin proteins in three diseases caused by fungi. The specific focus will be on hydrophobins from fungal species that cause severe loss of rice plants, cause invasive growths in humans, and infect the eggs of endangered turtles and result in death of the turtle embryos. Hydrophobins are small fungal proteins that assemble into large biological layers at the boundary between the fungus and the host. This research aims to focus on characterising the structure of the layers, understanding how they form and how they attach to the host tissue. This work may lead to new antifungal strategies aimed at reducing the impact of these devastating fungal infections.Read moreRead less
The ins and outs of HIV biology. This project aims to delineate the fundamental mechanisms that regulate the production of HIV and the ability of HIV to cause AIDS in infected patients. It will utilise state-of-the-art technologies to unearth new clues that govern the biology of HIV, with the ultimate goal to develop novel vaccine and treatment strategies against HIV.
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.
The molecular mechanism of bacterial ABC toxins. This project aims to establish that the ABC family of bacterial protein toxins, the main virulence factors in many species of naturally-occurring bacterial pathogens of insect pests, represent a protein machinery that cells and other organisms may use to deliver bioactive proteins to specific cells. ABC toxins are the main virulence factors in many species of naturally-occurring bacterial pathogens of insect pests. This project aims to establish t ....The molecular mechanism of bacterial ABC toxins. This project aims to establish that the ABC family of bacterial protein toxins, the main virulence factors in many species of naturally-occurring bacterial pathogens of insect pests, represent a protein machinery that cells and other organisms may use to deliver bioactive proteins to specific cells. ABC toxins are the main virulence factors in many species of naturally-occurring bacterial pathogens of insect pests. This project aims to establish that ABC toxins represent a new protein machinery that may be used more widely throughout cells and other organisms to direct the intercellular delivery of bioactive proteins in a highly cell-specific manner. The project expects these findings to enable the development of biopesticides based on ABC toxins, and generic intercellular protein delivery devices for biotechnological use.Read moreRead less
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.