The main focus of the research undertaken in my group is the discovery and development of novel bioactive molecules and their application in industrial and medical settings. Naturally produced chemicals are of fundamental importance in biological systems. Such chemicals are used to mediate interactions across all levels of biological hierarchy. Very often such diverse molecules are produced only in minute quantities. New or innovative organic syntheses not only provide access to sufficient quantities of these molecules but also their analogues. The access to various structurally-related analogues allows full assessment of their biological activity and mode of action, and offers opportunities to develop new therapeutic leads. The research is multi-disciplinary in nature and involves a combination of synthetic organic chemistry, molecular modelling and biological screening.
The emergence of multi-drug resistance in common human pathogens has highlighted the need to develop novel classes of antimicrobials for the treatment of human disease. A number of projects are available in this area focussing on a combination of organic synthesis, molecular modelling, and in vitro and in vivo antimicrobial screening. This project will develop novel antagonists of bacterial signalling pathways, which inhibit the regulatory quorum sensing communication pathways of bacteria, and will model the receptor-ligand interaction using the X-ray crystal structures of bacterial signal receptors e.g. Pseudomonas quinolone system (PQS).
(in collaboration with Prof. David StC Black, Dr Rajesh Kuppusamy UNSW)
The majority of conventional antibiotics used today share a common feature in that they act on specific molecular targets. Having very well-defined targets, these drugs act with a high degree of selectivity, minimizing unwanted side effects. However, a major limitation of antibiotics targeting a single receptor is the ease with which resistance can be developed. The central aim of this project is to design novel small molecular antimicrobial peptide (SMAMP) mimics based on glyoxylamides and anthranilamides, which disrupt the normal functioning of the membranes of the bacterial cell, and as a consequence allow the development of antimicrobial agents and gels with enhanced activity and the ability to bypass resistance mechanisms used by bacteria against other antibiotic types.
(in collaboration with Prof. Peter Lewis, University of Newcastle)
The enzyme RNA polymerase (RNAP) that transcribes DNA into RNA is highly conserved across species. However, the factors that regulate the activity of RNAP are target-specific. Therefore, the unique interaction of sigma factors with RNAP in bacteria represents an ideal target for the development of small molecules that can specifically inhibit this interaction3. In this project new molecules that target these essential protein-protein interactions will be rationally designed and synthesized, and evaluated for their antimicrobial efficacy. These new small molecules would represent lead compounds for the development of new antibiotics.
(in collaboration with Dr Daniel Wenholz UNSW)
The isoflavones are the largest and most widely studied class of phytoestrogens displaying potent and selective cytotoxicity against cancer cells, with low toxicity to healthy cells. During the past five years we have developed several new phenoxodiol conjugates with potent biological activities, and have also incorporated phenoxodiol in a cyclodextrin formulation, which shows increased aqueous solubility.
Furthermore we have covalently conjugated phenoxodiol to dextran to generate a new product with enhanced stability and efficacy. In addition, we have developed methodologies for the synthesis of novel analogues of fused flavonoid natural products, including dependensin, rottlerin and kamalachalcone A. The overall aim of the project is to synthesize novel heterocyclic analogues of isoflavones. The specific objectives of the proposal are to synthesize aza-isoflavone structural analogues and to evaluate their biological activity using in vitro assays to identify structure-activity relationships as a means of refining synthetic targets to ultimately develop lead candidates.
(in collaboration Dr Belamy Cheung and Prof Glenn Marshall CCIA, UNSW)
Neuroblastoma (NB) is the most common extracranial solid tumour in early childhood, and it accounts for approximately 8% of all paediatric cancer and 15% of childhood cancer mortality. Approximately 20% of all NB cases experience MYCN oncogene amplification and overexpression, which is related to poor prognosis. Although this suggests a new therapeutic option for NB, developing molecules that directly target at MYCN protein has been challenging due to its structure with no apparent pocket for small molecule binding, its nuclear location and potential side effects in normal proliferating tissues. Among the pathways that control MYCN stability, ubiquitination is the most prominent mechanism. De-ubiquitination prevents ubiquitination, in which the degradation of MYCN is inhibited. Ubiquitin specific proteases (USPs) are de-ubiquitinating enzymes (DUBs) that play an essential role in the stability of MYCN by de-ubiquitination. Downregulation of USP5 leads to suppression of tumour suppressor protein p53, and inhibition of USP5 restores cell cycle check point control, leading to the induction of apoptosis. Therefore, developing novel inhibitors for USP5 could be a significant advancement for NB therapy. The overall aim of this project is to synthesize new scaffolds for inhibiting for USP5 and test their in vitro and in vivo efficacy.
(in collaboration with Dr Frances Byrne and A/Prof Kyle Hoehn, BABS, UNSW)
Cancer is a major burden of disease, affecting the lives of tens of millions on a global scale. A hallmark feature of nearly all cancer cells is their altered metabolism of glucose compared to non-cancerous cells. Relative to most normal cells, cancer cells use a greater proportion of incoming glucose for non-oxidative purposes including the production of building blocks for cell division (lipid, DNA and protein), rather than oxidative pathways that produce carbon dioxide (CO2) in mitochondria. The goal of this proposal is to develop anticancer molecules that change cancer cell glucose metabolism to be more like that of non-cancerous cells. We have identified a small molecule that increases glucose oxidation and selectively kills cancer cells in vitro and in mice. The aim of this project is to generate new derivatives with enhanced activity and drug-like properties. The new compounds will be evaluated for anticancer activity in various cancer cell lines.
Flavones and isoflavones are two structurally related large and diverse groups of natural compounds with broad spectra of biological activities including antioxidant, anticancer, antiviral and anti-inflammatory properties. They are recognized as “privileged” medicinal chemistry molecular frameworks because they are commonly found in biologically active compounds that show drug-like characteristics. Rottlerin is a flavonoid isolated from the fruits of a medicinal plant, \Malloutus philippensis. Our group has reported the successful synthesis of rottlerin via the acid-catalysed reaction of 5,7,8-trimethoxyflavene. A number of projects are available in this area focussing on the design and synthesis of new azaflavone analogues of flavones and isoflavones in which the ring oxygen atoms are replaced by a nitrogen atom.
(in collaboration with Prof Denis O’Carroll and Prof Michael Manefield)
Per-and poly-fluoroalkyl substances (PFAS), a class of organofluorine compounds, are attracting intense regulatory scrutiny and public awareness due to their xenobiotic nature and adverse impact to health. PFAS contain extremely stable C-F bonds, have excellent stability, surface activity, oleophobic and hydrophobic properties, and are widely used as water and oil repellents (e.g. in carpets, leather, fire extinguishing agents, non-stick pans, food packaging and other fields). Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are the two most common PFAS with half-lives of 5.4 years and 3.8 years, respectively. PFASs are widely used and discharged worldwide, and a variety of PFAS can be detected in the environment, wildlife and in humans. It is now known that PFAS bioaccumulate, biomagnify and are linked to immune suppression and cancer. In this project, we aim to create a platform that combines a sorbent and redox active catalysts (RACs) to remediate PFAS.
(in collaboration with Prof Mark Willcox, OPTOM, UNSW)
The use of medical devices has increased immensely over the last decade. Although, this increase in device use has resulted in a better quality of life and longer patient survival, device-related bacterial infections have emerged as a serious problem with the increased use of medical implants. Once in an established biofilm, bacteria are more resistant to antibiotic treatment and the host immune system. The aim of this project is to develop methodologies for the covalent attachment of novel anti-microbial compounds including specially designed peptide mimics or small heterocyclic compounds onto biomaterial surfaces. Initially the attachment chemistry will be optimised using glass as a model surface, and subsequently the methodology will be adapted for biomaterial surfaces. The resulting biomaterials will be characterised by various surface analysis techniques including XPS and ATR spectroscopy, and assessed for anti-microbial efficacy in collaboration with the microbiology partners.
(in collaboration with Prof Serkan Saydam, and Prof Michael Mansfield UNSW)
Microorganisms are known to threaten the longevity of many engineered structures. Previous studies have shown that acidic solutions containing hydrogen sulphide (H2S) can cause hydrogen-induced SCC (HISCC) also known as hydrogen embrittlement (HE). Microorganisms, particularly Sulphate Reducing Bacteria (SRB) present in the mines, produce H2S that resulting in Microbiologically Induced Stress Corrosion Cracking (MISCC). In this project we aim to develop prevention measures, such as antimicrobial coatings against SRB, as a long-lasting controlling technique to mitigate against MISCC in underground mines.
(in collaboration with Prof Mark Willcox, Prof Bill Walsh, Dr Renxun Chen UNSW)
The COVID-19 pandemic has occurred through the transmission of the SARS-CoV-2 virus worldwide. All infection control strategies are focussed on reducing the transmission of the virus. Transmission routes for SARS-CoV-2 are through aerosols of respiratory secretions and via contamination of surfaces. Whilst there are currently several vaccines that prevent a person becoming seriously ill with the virus and reduce the load of virus within individuals, there is still uncertainty on how quickly they can be deployed to control the spread of the disease around the world. This means strategies for reducing transmission of the virus may well be in place for many years to come. The main aim of this project is to develop disinfection strategies to decontaminate surfaces and equipment for reuse or recycling.
(in collaboration with Prof Mark Willcox, Dr Renxun Chen UNSW)
There is an imperative to develop environmentally compatible strategies to control bacterial biofilms on industrial surfaces. For example, biofilm mediated corrosion affects a range of industries, from oil distribution to food processing surfaces and has been estimated to result in added costs of between US$20-300 billion per year in the USA alone. Biofilms also form on membrane surfaces, such as in reverse osmosis plants, where the associated biomass block the membrane pores. Fouling increases the water pressure required to continue filtration, significantly increasing the cost of water purification. When fouling occurs, water purification systems must be shut-down for chemical disinfection and back flushing to alleviate fouling. The current state of the art for the removal of biofilms from pipelines, membranes and food handling surfaces typically include either alone or in combination, mechanical scrubbing, such as ‘pigs’ or brushes as well as harsh chemicals, many of which are highly toxic, such as glutaraldehyde. These low-tech approaches are typically not effective at removing biofilms which are significantly more resistant than free living bacteria.
Recently, it has been shown that by exogenously adding small molecules that generate nitric oxide (NO), generically called NO donors, it is possible to induce the dispersal of surface associated bacteria and biofilms in a number of bacteria. The aim of this project is to deliver nitric oxide (NO) donating molecules directly on surfaces using coatings or co-polymers for the control of biofilms on surfaces.