Perugini - Rational inhibitor design targeting drug-resistant bacteria, noxious weeds, and common age-related diseases
Resistance to common antibiotics and herbicides is on the rise. There is thus an urgent need to discover new anti-microbial and anti-herbal agents, and an equally urgent need to characterise new drug targets. The Perugini laboratory studies the structure, function, regulation and inhibition of essential oligomeric enzymes, such as dihydrodipicolinate synthase (DHDPS), from the diaminopimelate biosynthesis pathway of bacteria & plants. Given their essentiality and multivalent nature, these oligomeric enzymes serve as excellent targets for the development of new anti-infection therapeutics and agrichemicals.
The Perugini lab is also interested in characterising the role of apolipoprotein E (apoE) in cardiovascular and Alzheimer’s disease. With these diseases accounting for approximately 30% of all deaths in Australia, effective intervention strategies for the treatment or prevention of cardiovascular and Alzheimer’s disease are urgently required. Studying the structure, function, and interactions of human apoE will provide insights into the development of such therapies.
New inhibitors targeting bacterial and plant DHDPS
This project involves testing the in vitro and in vivo potency of small drug-like compounds targeting 'druggable' sites of the essential bacterial enzyme, dihydrodipicolinate synthase (DHDPS). The project will foster the development of multidisciplinary skills including recombinant protein expression and purification, enzymology, analytical ultracentrifugation, circular dichroism spectroscopy, computational design, isothermal titration microcalorimetry, mass spectrometry, microbiological viability assays, microscale thermophoresis, plant molecular biology (in collaboration with Dr Anthony Gendall from AgriBio), X-ray crystallography (in collaboration with Dr Santosh Panjikar from the Australian Synchrotron) and medicinal chemistry (in collaboration with Dr Belinda Abbott from the Department of Chemistry and Physics, La Trobe University). This project will be co-supervised by NHMRC Early Career Fellow Dr Tatiana Soares da Costa.
Role of apoE in late-onset Alzheimer’s and cardiovascular disease
One of the major risk factors associated with cardiovascular and Alzheimer's disease is apolipopprotein E (apoE). ApoE exists as three major isoforms that differ due to single amino acid substitutions at positions 112 and 158. ApoE3 (112C158R) is the most common isoform and is associated with a healthy state; whereas apoE2 (112C158C) and apoE4 (112R158R) are strongly linked to an increased risk of developing type III hyperlipoproteinemia and late-onset Alzheimer's disease, respectively.
This project aims to compare the structure, function and protein-protein interaction networks of apoE isoforms using analytical ultracentrifugation, isothermal titration microcalorimetry, lipid binding assays, mass spectrometry, microscale thermophoresis, molecular dynamics simulations (in collaboration with Dr Matthew Downton and Dr John Wagner from IBM) and X-ray crystallography (in collaboration with Dr Luke Miles and Prof Michael Parker from St Vincent's Institute of Medical Research).
Meet the team
NHMRC ECR fellow
Matthew Boarder (co-supervised by Dr Tatiana Soares da Costa)
Cody Hall (co-supervised by Dr Tatiana Soares da Costa)
Rachael Impey (co-supervised by Dr Tatiana Soares da Costa)
Emily Mackie (co-supervised by Dr Tatiana Soares da Costa)
Mitchell Azlin (co-supervised by Dr Tatiana Soares da Costa)
Ayden Kelly (co-supervised by Dr Tatiana Soares da Costa)