Matt Perugini
Structure, function and inhibition of bacterial lysine biosynthetic enzymes
The primary research program of the Perugini laboratory focuses on the structure and function of bacterial enzymes involved in lysine biosynthesis, with particular emphasis on the quaternary structure, activity, and inhibition of dihydrodipicolinate synthase (DHDPS, Fig. 1A) and dihydrodipicolinate reductase (DHDPR, Fig. 1B). DHDPS and DHDPR catalyse essential steps in the lysine biosynthetic pathway of bacteria, which humans lack, and therefore are suitable as potential antibiotic targets. Currently, the lab is offering Honours and/or PhD projects aimed at characterizing the structure, function and inhibition of DHDPS and DHDPR from Bacillus anthracis, Clostridium botulinum, drug-resistant Streptococcus pneumoniae (DRSP), and methicillin-resistant Staphylococcus aureus (MRSA). Recent work in the Perugini laboratory has demonstrated that a “triple-pronged” approach can be employed to inhibit DHDPS and DHDPR, which offers insight into the development of novel drugs targeting these essential enzymes. The major techniques employed in this research program include analytical ultracentrifugation, X-ray crystallography, enzyme kinetics, molecular biology, protein expression and purification, mass spectrometry, circular dichroism spectroscopy, and fluorescence spectroscopy. The multidisciplinary program involves collaborations with several local and international research groups, including Prof Juliet Gerrard’s laboratory (University of Canterbury, New Zealand), Dr Craig Hutton’s group (Bio21 Institute), and Prof Michael Parker (St Vincent’s Institute, Melbourne). The Perugini lab is therefore seeking enthusiastic researchers with a keen interest in developing expertise in structural biochemistry, enzymology, and drug discovery.
Fig. 1 Ribbon structures of (A) bacterial DHDPS and (B) DHDPR
Biomarker discovery in age-related disease
In collaboration with Dr Paul Baird from the Centre for Eye Research Australia (CERA), the Perugini laboratory is also involved in a discovery program that aims to identify protein biomarkers for age-related macular degeneration (AMD). AMD is characterised by the deposition of drusen in the macular of the eye as shown in Fig. 2. Given that AMD is a leading cause of blindness and visual loss in adults, particularly the elderly, the discovery of markers for the disease will result in better detection methods, improved treatment, and decreased financial burden for patients and their families. This project employs key proteomic platform technologies, namely two-dimensional differential in-gel electrophoresis (2D DIGE) and mass spectrometry, coupled to standard protein chemistry techniques (eg ELISA and Western blotting) to detect and quantitate protein markers in human plasma.
Fig. 2 (A) Cross-sectional view of the human eye, (B) close-up of the macular region of the retina in AMD
Lab personnel
HeadDr Matt PeruginiResearch staffDr Renwick Dobson (CR Roper Fellow)Dr Con Dogovski (Post-doctoral fellow) Jarrod Voss (Research assistant) Graduate studentsLauren Angley Honours students
Tanzeela Siddiqui |
Selected references
- Griffin MDW, Dobson RCJ, Pearce FG, Antonio L, Whitten AE, Liew CK, Mackay JP, Trewhella J, Jameson GB, Perugini MA, Gerrard JA. (2008) 'Evolution of quaternary structure in a homotetrameric protein'. J Mol Biol, 380(4), 691-703.
- Hutton CA, Perugini MA, Gerrard JA. (2007) 'Inhibition of lysine biosynthesis: an emerging antibiotic strategy'. Mol BioSyst, 3, 458–65.
- Gerrard JA, Hutton CA, Perugini MA. (2007) 'Inhibiting protein-protein interactions as an emerging paradigm for drug discovery'. Mini Rev Med Chem, 7, 151–7.
- Perugini MA, Griffin MDW, Smith BJ, Webb LE, Davis AJ, Handman E, Gerrard JA. (2005) 'Insight into the self-association of key enzymes from pathogenic species'. Eur Biophys J, 34, 469–76.