Inhibitors Of Bacterial Protein Synthesis - A New Class Of Antibiotics
Funder
National Health and Medical Research Council
Funding Amount
$120,000.00
Summary
Pioneering work by CSIRO scientists has identified specific peptide motifs in the DNA replication machinery of bacteria that are critical for the correct functioning of the organism. In collaboration with CI Alewood potent (Kd ~ nM) lead compounds that inhibit bacterial DNA replication have been designed and synthesised. Through the application of a number of novel bioinformatics approaches to the analysis of the complete genome sequences of bacteria, the key sites of interaction of a number of ....Pioneering work by CSIRO scientists has identified specific peptide motifs in the DNA replication machinery of bacteria that are critical for the correct functioning of the organism. In collaboration with CI Alewood potent (Kd ~ nM) lead compounds that inhibit bacterial DNA replication have been designed and synthesised. Through the application of a number of novel bioinformatics approaches to the analysis of the complete genome sequences of bacteria, the key sites of interaction of a number of protein families (DNA synthesis and repair enzymes) with the beta subunit of bacterial DNA Polymerase III have been identified. The nature of the sites, and preliminary experimental data, suggests that the approach will be generally applicable to all species of bacteria. In addition a wide range of novel assays for the identification of inhibitors of the interaction of proteins with the beta subunit have been developed. In this proposal we wish to demonstrate that our in vitro nanomolar inhibitors of the beta subunit can inhibit bacterial cell growth. The development program proposes to develop methods and strategies to gain bacterial cell entry of inhibitors of the interaction of proteins with the beta subunit of bacterial DNA Polymerase III. Proof of concept will be demonstrated by inhibition of bacterial cell growth. Stable compounds with good binding characteristics and able to be taken up by cells will be developed based on structure-function assay results, structural studies and modelling of inhibitors bound to the target. Antimicrobial activity of compounds will be demonstrated in standard FDA approved NCLLS (National Centre of Clinical Laboratory Standards USA) tests. Spectrum of activity will be demonstrated by testing compounds against bacterial species representative of the range of pathogenic organisms in standard FDA assays.Read moreRead less
Structural And Biochemical Investigation Of The Bloom�s Complex, Defective In Bloom�s Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$184,661.00
Summary
Bloom�s Syndrome is a rare inherited disorder that results in greater than 90% risk of developing cancer by the age of 25. The gene that causes Bloom�s Syndrome, called BLM, protects cells from cancer-causing mutations hence affected individuals develop the same types of cancers as the general population, only much faster. We will investigate the properties of the BLM gene product and understand how it protects us from cancer, and may influence some forms of cancer treatment.
Biochemical Reconstitution Of The Ubiquitin Ligase Pathway Defective In Fanconi Anaemia
Funder
National Health and Medical Research Council
Funding Amount
$562,742.00
Summary
Fanconi Anemia (FA) is characterised by loss of vital blood cells but also 700x risk of developing leukaemia and other cancers. FA is caused by an inherited defect in one of 15 different genes that provide a signal and repair mechanism protecting cells from cancer causing mutations. By reconstructing this signaling mechanism in the test tube we will determine how it contributes to cancer protection, and highlight potential strategies for treatment of FA and leukaemia in the general population.
Regulation And Function Of The Zinc-finger Protein ASCIZ In The DNA Damage Response
Funder
National Health and Medical Research Council
Funding Amount
$640,101.00
Summary
Each human cell is exposed to more than 10,000 spontaneous DNA damage events per day. Inaccurate repair of this is damage is believed to be one of the key events in the onset of cancer. We have discovered a protein called ASCIZ that contributes to the repair of DNA base damage, and also has a separate function in the onset of lung development. Here we want to study in detail the mechanism of how it functions in DNA repair and thereby keeps mutation rates low and prevents the onset of cancer.
Understanding And Controlling PAS Domain Interactions In Basic Helix-loop-helix Transcription Factors
Funder
National Health and Medical Research Council
Funding Amount
$599,918.00
Summary
We want to understand how particular proteins control the activity of genes that are a crucial part of the body's ability to respond to environmental stresses, such as low oxygen, seizure and environmental pollutants. The knowledge gained will help decipher the events that result in correct function in the cell, and the misregulation that leads to toxic outcomes and disease states. We will search for new compounds with potential application as therapeutics for cancer, heart disease and stroke.
Multi-domain Regulation Of DNA Damage Response Kinases
Funder
National Health and Medical Research Council
Funding Amount
$313,427.00
Summary
DNA damage plays a key role in the onset of cancer and the response to cancer therapies. Mutations in the Chk2 DNA damage response kinase are associated with increased cancer risk. We will study detailed mechanisms how phosphorylation of Chk2-like kinases contributes to normal copying of our DNA every time a cell divides, and how it regulates how Chk2 is activated. The studies will improve our understanding how cancer may originate and how cancer cells respond to chemo- or radiation therapy.
Targeting Lagging Strand DNA Replication In Model And Pathogenic Bacteria
Funder
National Health and Medical Research Council
Funding Amount
$590,426.00
Summary
An increasing concern is the growing number of hospital acquired infections that cannot be treated effectively with antibiotics because the bacteria that cause them are resistant to drug treatments. This project will develop our basic understanding of how DNA is copied in bacteria that are about to reproduce themselves, and we will use this knowledge to discover ways to stop them from copying their DNA, thus killing them. This will provide the foundation for development of new antibiotics.
FHA Domain-dependent Functions Of Cell Cycle Checkpoint Kinases
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
Human chromosomes as carriers of the genetic information are constantly subjected to DNA damage. This usually occurs spontaneously, simply as a result of oxidation of DNA residues as a byproduct of cellular energy consumption or as a result of errors during chromosome duplication in growing cells, and is compounded by chemical or physical agents, for example carcinogens, UV rays or X-rays. DNA damage can have severe consequences if not properly repaired, leading to genomic instability with loss ....Human chromosomes as carriers of the genetic information are constantly subjected to DNA damage. This usually occurs spontaneously, simply as a result of oxidation of DNA residues as a byproduct of cellular energy consumption or as a result of errors during chromosome duplication in growing cells, and is compounded by chemical or physical agents, for example carcinogens, UV rays or X-rays. DNA damage can have severe consequences if not properly repaired, leading to genomic instability with loss of vast tracts of DNA or inappropriate genome rearrangements, that may ultimately give rise to cancer. To prevent such dire consequences, all organisms from yeast to man contain molecular checkpoints that sense the presence of DNA damage and then activate a cellular response program that includes damage repair and prevention of cell division while damage persists. These molecular checkpoints are highly conserved throughout evolution which allows us to analyse the details involved in simple organisms such as yeast, to draw general conclusions on their function in more complex human cells. Along these lines, we are studying the function of two yeast proteins that are similar to the human Chk2 protein, a tumour suppressor that is mutated in a subset of families suffering from the Li-Fraumeni multi-cancer syndrome. We have identified new pathways by which these proteins contribute to the survival of cells after treatment with DNA damaging agents and will further charaterise these in the present proposal.Read moreRead less
Role Of FHA Domains As Protein-protein Interaction Modules In Cell Signalling
Funder
National Health and Medical Research Council
Funding Amount
$191,973.00
Summary
The proper processing of information in cells involves the association of different proteins to signalling complexes. We will decipher the role the so-called FHA module plays in the formation of protein complexes. FHA modules are present in several proteins that are important for the repair of damaged DNA and the stability of chromosomes. Understanding the structure and function of this module will be relevant for various forms of cancer where DNA is damaged.