Antimicrobial probiotics and mechanism study

Probiotics are living non-pathogenic microorganisms that confer a health benefit and improve physiological conditions in the host when administered in adequate amounts.  The inclusion of probiotic in animal feeds have proven to be beneficial to animal health. The project is a collaborative research program between Griffith University and Bioproton, aiming at investigating the mechanism of action of probiotics that have antimicrobial activity. The outcome of the project will lead to scientific discovery on the antimicrobial behaviours of probiotics.  The active Bacillus strains can be used as effective antimicrobial agent in animal feed materials.

Primary supervisor: A/Prof Yun Feng

Other supervisor: Dr Wendy Chen (external - Bioproton Pty Ltd)

To apply: Contact A/Prof Yun Feng with your CV at y.feng@griffith.edu.au

The use of natural product scaffolds in the generation of novel chemical libraries for drug discovery and chemical biology research

Natural products display chemical complexity and diversity often not seen in synthetic library collections and they inherently interact with biomolecules (e.g. enzymes/proteins, DNA), making them an ideal source of unique scaffolds for screening library generation. Core ring structures found in natural products are not present in commercial collections. By using natural product scaffolds we can generate chemically diverse libraries that can subsequently be used in drug discovery programs or molecular probe research. This project aims to create unique chemical libraries that can be tested against a range of biological targets. Isolation chemistry (e.g. HPLC, MPLC, gel permeation chromatography) will be undertaken on plant or marine samples obtained from the NatureBank biota repository in order to obtain scaffolds of interest, and then synthetic reactions (e.g. amidations, reductive aminations, late stage functionalisation) will be used to generate the novel chemical libraries. Spectroscopic techniques (e.g. 1D/2D NMR, MS, IR, UV) will be used for the structure elucidation and characterisation of all synthesised compounds. This project will result in the generation of unique compound libraries that will impact drug discovery or chemical biology research.

Primary supervisor: A/Prof. Rohan Davis

Other supervisors: Prof. Colleen Nelson (QUT), A/Prof. Ian Tietjen (Penn State)

To apply: Contact A/Prof. Rohan Davis with your CV at r.davis@griffith.edu.au

Hunting for new alkaloids using NatureBank’s Eremophila plant collection

Humans have utilised alkaloid-containing plants since the dawn of time for therapeutic purposes. Modern drug discovery research on many of these plants has identified important and well-known alkaloid drugs including morphine, vinblastine, scopolamine, atropine, cocaine, quinine, physostigmine, and theophylline, to name but a few. While >200 secondary metabolites have been isolated from the endemic Australian plant genus Eremophila, only three of these natural products contain nitrogen, the cyanoglycosides mandelonitrile β-sophoroside and prunasin, and the quinoline-serrulatane, microthecaline A that was recently reported by the Davis group at GRIDD. The discovery of microthecaline A has initiated a natural product research program using the NatureBank plant library in order to identify new alkaloids from these under-investigated desert plants. This project will result in the characterization of new compounds both chemically and biologically and will impact either drug discovery or chemical biology.

Primary supervisor: A/Prof. Rohan Davis

Other supervisors: Prof. Colleen Nelson (QUT/TRI), A/Prof. Ian Tietjen (Penn State)

To apply: Contact A/Prof. Rohan Davis with your CV at r.davis@griffith.edu.au

Discovery of new anthelmintic drugs from the sea

Nature provides unlimited inspiration for innovation in the agrochemical sector. The Nobel Prize-winning discovery and development of the anti-parasitic drugs avermectin and artemisinin has renewed interest in exploring natural products for additional new anthelmintic drug leads that will impact and benefit agri-business. Due to the widespread occurrence and spread of anthelmintic resistance, there is an urgent need to develop new drugs against resistant parasitic nematodes of livestock animals.

NatureBank, housed at the Griffith Institute for Drug Discovery at Griffith University, is Australia’s largest biodiscovery resource currently comprising ~30,000 plant, fungi and marine invertebrate samples. Importantly, this unique collection of Australian biota has been processed into ready-to-screen extract and fraction libraries. A collaboration between A/Prof. Rohan Davis (Griffith University) and Prof. Robin Gasser, (Melbourne University) has resulted in the screening of the NatureBank marine extract library (~8,000 extracts) in order to identify samples that have in vitro activity against the barber's pole worm, Haemonchus contortus, a highly significant pathogen of ruminants. HTS has identified several hit extracts, which require follow-up chemistry in order to determine the bioactive compounds within the hit extract.

This research will identify new marine natural products with anthelmintic potential from Australian marine invertebrates and will result in the characterization of these compounds both chemically and biologically, ultimately impacting the animal health drug pipeline.

Primary supervisor: A/Prof. Rohan Davis

Other supervisors: Prof. Robin Gasser (Melbourne University)

To apply: Contact A/Prof. Rohan Davis with your CV at r.davis@griffith.edu.au

Lighting up malaria parasite DNA

Chemical probes are small molecule reagents that are used by researchers to dissect fundamental biological processes in living cells, such as DNA synthesis that is central to all dividing cells. The aim of this project will be to develop a panel of high quality chemical probes to allow quantitative monitoring of DNA synthesis in Plasmodium (malaria) parasites. Malaria is responsible for the deaths of over 400,000 people annually, largely affecting children under five years of age and pregnant women. Current chemical probes for this significant infectious disease have been repurposed from mammalian cell use, malaria-specific probes will assist studies aimed at understanding the effect of potential new antimalarial therapies. State-of-the art image-based technologies will be used to track the parasites treated with the chemical probes. This project is at the interface of chemistry and biology and you will learn a rare combination of skills across the chemical biology discipline.

Primary supervisor: Prof Sally-Ann Poulsen

Other supervisors: Prof Vicky Avery, Dr David Hilko

To apply: Contact Prof Sally-Ann Poulsen with your CV at s.poulsen@griffith.edu.au

Unravelling the genomic dark matter: the key to precision medicine for neurological disorders

Neurological disorders such as Parkinson’s disease, dementia and schizophrenia are caused by a ‘perfect storm’ of unique combinations of genetic and environmental factors. Such complex combination of events leads to disruptions in gene networks and biological pathways that alter cell functions and consequently influence disease risk. We now know that over 90% of genetic variation associated with these disorders are not in protein-coding genes but in regulatory regions of the genome (previously considered to be junk DNA). This ‘junk DNA’ contains regulatory elements that precisely coordinate molecular processes to determine how specific cells and tissues work. New approaches in genomic technologies, computational models and experimental systems could potentially lead to personalised treatment based on an individual’s genetic composition. This project aims to map molecular networks and cell functions affected in patient-derived stem cells to help discover new therapeutic strategies tailored based on patient’s molecular and cellular signatures.

Primary supervisor: Dr Alex Cristino

Other supervisors: A/Prof Stephen Wood, Prof Emeritus Alan Mackay-Sim

To apply: Contact Dr Alex Cristino with your CV at a.cristino@griffith.edu.au

Identifying Biomarkers for Parkinson’s Disease as a Step toward a Cure

Parkinson’s disease (PD) is a complex, incurable, multifactorial neurological condition affecting over 65,000 Australians with an economic burden of $10 billion per annum. With an aging population the disease related costs will rise unless we find better ways to identify those at risk, provide early diagnosis and treat the disease from an understanding of its causation in each individual. The development of robust biomarkers is essential to meeting these challenges. No biomarkers are available which is the major impediment to progress towards a cure. We have developed a cell model of PF using patients’ own cells. Subjecting the cells to chemical stress reveals a different response between cells from PD patients and those from healthy individuals. We have several projects examining how we can use these stress tests to identify the underlying disease trigger in each patient. This is the first step toward personalised medicine for PD.

Primary supervisor: A/Prof Stephen Wood

Other supervisor: Prof George Mellick

To apply: Contact A/Prof Stephen Wood with your CV at s.wood@griffith.edu.au

Bioinspired Polymeric Particles as Next-Generation Drug Delivery Platform

The FDA-approved polyhydroxybutyrate self-assembles in engineered bacteria and forms spherical particles of approximately 200 nm in diameter. Such particles composed of polymeric core and protein shell are of considerable interest as drug carrier platform due to its process scalability, biocompatibility, and core–shell structural functionality coupled with the rich chemistry of the shells. The unique design space and material properties provided by these bioinspired particles will be harnessed by exploring the ability to retain high-capacity loading of drugs at the core. Novel physicochemical properties will be engineered into the shell surface through genetic and chemical modification to obtain hybrid organic-inorganic core-shell particles with controlled physical properties and targeting ability. As a proof-of-concept, these multifunctional carrier systems will be used for oral drug delivery against devastating colorectal cancer.

Primary supervisor: Prof Bernd Rehm

Other supervisor: Dr David Wibowo

To apply: Contact Prof Bernd Rehm with your CV at b.rehm@griffith.edu.au

Reversing drug resistance in multiple myeloma, an incurable cancer of the bone marrow

A two-drug combination therapy where the first drug targets the diseased cell and the second drug targets the cell's resistance mechanism to the first drug is an underexplored approach to combat or prevent drug resistance in cancer. The aim of this project is to characterize the relationship between a series of proteins that we propose is responsible for drug resistance in multiple myeloma (MM), an incurable cancer of the bone marrow. Without treatment, typical survival is 7 months; while drug treatment with bortezomib increases median survival to 4-5 years. Drug resistance to bortezomib is however inevitable. We propose to target this mechanism with a two-drug combination therapy by developing new small molecules that will improve the response of MM to bortezomib. This is a chemical biology project – involving the development of medicinal chemistry and biochemistry skills and expertise. A two-drug combination therapy where the first drug targets the diseased cell and the second drug targets the cell’s resistance mechanism to the first drug is an underexploited approach to combat or prevent drug resistance in cancer.

Primary supervisor: Prof Sally-Ann Poulsen

Other supervisors: A/Prof Kathryn Tonissen, Dr David Hilko

To apply: Contact Prof Sally-Ann Poulsen with your CV at s.poulsen@griffith.edu.au

Decoding the Language of Nature: Is it time for Artificial Intelligence to predict the function of natural products based on structure

The project will address one of chemistry’s grand challenges: to find a function for every metabolite produced by Nature.

The aim is to develop a method to predict the function of a compound produced by nature by looking at its chemical structure. Technological advances in artificial intelligence (AI), especially in the field of deep learning, hold the potential to make smart predictions based on explainable knowledge and patterns. Multi-faceted Big Data on the function of metabolites offers exciting new opportunities to apply state-of-the-art deep learning advances to pursuing the grand challenge of predicting biological function from the chemical structure of a metabolite.

We will address the questions: 

  • What scaffolds are embedded in bioactive natural products?
  • What fragments occur in larger natural products?
  • What similarity exists between proteins detected by fragment-based approaches and other target ID methods.
  • How can the information be used in AI?

Primary supervisor: Prof Ron Quinn

Other supervisors: Dr Can Wang, Dr Miaomiao Liu

To apply: Contact Prof Ron Quinn with your CV at r.quinn@griffith.edu.au

Lighting up giardia parasite DNA

Chemical probes are small molecule reagents that are used by researchers to dissect fundamental biological processes in living cells, such as DNA synthesis that is central to all dividing cells. The aim of this project will be to develop a panel of high quality chemical probes to allow quantitative monitoring of DNA synthesis in Giardia parasites. Giardia parasites cause giardiasis a common but neglected parasitic disease that causes wide-spread morbidity and disadvantage. On an annual basis Giardia parasites infect ~1 billion people of which >200 million develop symptomatic disease. Current chemical probes for this infectious disease have been repurposed from mammalian cell use and there is a need to develop parasite specific tools to support advances Giardia research. State-of-the-art image-based technologies will be used to track parasites treated with chemical probes. This project is at the interface of chemistry and biology and you will learn a rare combination of skills across the chemical biology discipline.

Primary supervisor: Prof Sally-Ann Poulsen

Other supervisors: A/Prof Tina Skinner-Adams, Dr David Hilko

To apply: Contact Prof Sally-Ann Poulsen with your CV at s.poulsen@griffith.edu.au

Target Identification using Native Mass Spectrometry: Tuberculosis

At the heart of this project is an innovative use of native mass spectrometry to detect complexes between small molecules and proteins of therapeutic relevance to establish an advanced platform for accelerated drug discovery. The primary challenge for developing drugs is the identification of the protein target. Native mass spectrometry offers the potential to identify specific protein targets as opposed to most other techniques that identify lists of putative targets. Tuberculosis is the 10th leading cause of death worldwide. It is the main cause of death from any infectious disease, ranking above HIV/AIDS. In the laboratory, we will investigate anti-TB compounds identified following a high throughput screen of 200,000 natural product fractions and from traditional Chinese medicines used to treat TB to answer the following questions: 

  • How much protein purification is required to identify drug targets in complex mixtures of proteins using native mass spectrometry?
  • What is the mechanism of action of anti-TB natural products?

Primary supervisor: Prof Ron Quinn

Other supervisors: Dr Miaomiao Liu, Dr Tianyu Zhang (external - Chinese Academy of Sciences), Prof Yang Ye (external - SIMM)

To apply: Contact Prof Ron Quinn with your CV at r.quinn@griffith.edu.au

Finding better compounds to develop as drugs using mass spectrometry

Finding appropriate compounds to develop as drugs is one of the major challenges for drug discovery research but is the heart of any successful drug discovery campaign. ‘Fragments’ are very small molecules that bind weakly to proteins. They have been shown to be excellent starting points for drug discovery (with three approved drugs derived from fragments in recent years) yet are difficult to detect. An essential pillar of fragment based drug discovery (FBDD) is thus the detection of weak binding fragments. Sensitive biophysical screening methods must be used such as NMR, X-ray crystallography, or surface plasmon resonance (SPR). In this project native state mass spectrometry (MS), a powerful technique for studying proteins in their folded state, will be applied for fragment screening. This is a collaborative project with Takeda California and you will spend 12 months of your PhD in industry. This project will identify fragments and determine the fragment binding constants for therapeutic proteins in Takeda’s target portfolio. These targets will include both soluble proteins and membrane proteins.

Primary supervisor: Prof Sally-Ann Poulsen

Other supervisors: Dr Maria Halili, Dr Pedro Serrano (external - Takeda)

To apply: Contact Prof Sally-Ann Poulsen with your CV at s.poulsen@griffith.edu.au

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