Centre for Chemistry and Drug Discovery - Projects List
Biosynthesis of circular antimicrobial peptides
Principal Advisor: Dr Conan Wang (IMB)
Associate Advisor: Prof David Craik (IMB); Prof Ian Henderson (IMB); Dr Thomas Durek (IMB)
Circular proteins are modified in a post-translational reaction that covalently joins their N- and C-termini. Deciphering the underlying biochemical reactions may lead to the development of new drugs that are more stable and potent and may provide new tools for protein and peptide engineering. Circular bacteriocins are a unique class of these biomolecules produced naturally by bacteria and have exhibited promising activities against a wide range of refractory pathogens in both the clinic and food industry. This project aims to reveal the secrets of how certain bacterial cells produce these proteins, how they protect themselves from the effects of these antimicrobials and how these molecules kill susceptible strains.
We encourage candidates with a strong background and interests in microbiology, biochemistry and/or molecular biology and who are interested in working in a diverse research environment, to apply. The host laboratory is embedded within the ARC Centre of Excellence for Innovations in Peptide and Protein Science, and therefore there are many opportunities to collaborate with scientists nationally and internationally. The project will involve whole-genome genetic manipulations, biochemistry, structural biology, biophysics and analytical chemistry. The project will lead to a better understanding of how some of nature’s most unique proteins are produced and could lead to new industry partnerships.
*Characterisation of blood-brain barrier nutrient transporters
Principal Advisor: Dr Rosemary Cater (r.cater@uq.edu.au)
Associate Advisor: Dr Anne Lagendijk (a.lagendijk@imb.uq.edu.au)
The blood-brain barrier (BBB) is a layer of tightly packed endothelial cells that separate the blood for the brain. The BBB has evolved to protect our brains from blood-borne neurotoxins and pathogens, but unfortunately, it also prevents the majority of potential neurotherapeutics from entering the brain. In fact, it has been estimated that ~98% of all small-molecule drugs are not able to cross the BBB. This creates a major bottleneck in the development of treatments for diseases such as Parkinson’s disease, Alzheimer’s disease, glioblastoma, anxiety, and depression. The more we know about what can enter the brain, the better informed we will be for developing treatments for these diseases. Transporter proteins expressed at the BBB play a very important role in regulating the entrance of molecules in a highly specific manner. For example, the transporters FLVCR2 and MFSD2A allow for the uptake of choline and omega-3 fatty acids into the brain – both of which are essential nutrients that the brain requires in very large amounts. This project will utilise biochemical techniques and structural biology (cryo-EM) to further understand transport proteins at the BBB and how they transport specific molecules into the brain. This will provide critical insights that for the development of neurotherapeutics that can hijack these transporters to allow for entrance into the brain.
*Qualifies for the Global Challenges Scholarship.
Deconstructing the genetic causes of disease to discover new drug targets
Principal Advisor: A/Prof Nathan Palpant (IMB)
Associate Advisor: Dr Andrew Mallett (IMB); Dr Sonia Shah (IMB), Dr Mikael Boden (UQ School of Chemistry and Molecular Biosciences)
Industry partnership opportunities: HAYA Therapeutics; Maze Therapeutics
Despite strong vetting for disease activity, only 10% of candidate new drugs in early-stage clinical trials are eventually approved. Previous studies have concluded that pipeline drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. This project will take advantage of increasing clinical disease data, rapid growth in GWAS datasets, drug approval databases, and innovative new computational methods developed by our team. The overall goal is to develop unsupervised computational approaches to understand what genetic models and data are most predictive of future drug successes. Underpinning this work, the project will build and implement computational and machine learning methods to dissect the relationships between genome regulation, disease susceptibility, genetic variation, and drug development. The project will not only reveal fundamental insights into genetic control of cell differentiation and function but also facilitate development of powerful unsupervised prediction methods that bridge genetic data with disease susceptibility and drug discovery. Students with background/expertise in computational bioinformatics and machine learning are ideal for this work. Informed by clinical, computational, and cell biological supervisory team, the project will have an opportunity to engage with diverse international companies through internships and collaborations to facilitate co-design of these methods for uptake in industry discovery and prediction pipelines.
Developing Models of Cancer Therapy-Induced Late Effects
Principal Advisor: Dr Hana Starbova (IMB)
Associate Advisor: Prof Irina Vetter (IMB; UQ School of Pharmacy); Dr Raelene Endersby (Telethon Kids Institute)
Treatments such as radiotherapy and chemotherapy for childhood and adult brain cancers save many lives. However, they also cause long-term debilitating adverse effects, also termed "late effects", such as pain, cognitive disabilities and sensory-motor neuropathies. Currently, no effective treatments are available, and brain cancer survivors are forced to live with long-term disabilities.
Animal models are important for the understanding of disease pathology and for preclinical testing of novel treatment strategies. However, currently there are no appropriate animal models available for the testing of late effects of cancer therapy.
To address this gap, this PhD project aims to develop in-vivo animal models of cancer therapy-induced late effects and to test the efficacy of novel treatment strategies. This project forms a foundation for future clinical studies.
Animal handling and behavioural assessments in rodents are vital for this project.
Developing new drugs targeting acid sensitive channels to treat ischemic heart disease
Principal Advisor: Prof Nathan Palpant (IMB)
Associate Advisor: Prof Jennifer Stow (IMB); Prof Brett Collins (IMB); A/Prof Markus Muttenthaler (IMB)
Industry partnership opportunities: Infensa Bioscience
This project focuses on strategies to prevent organ damage associated with ischemic injuries of the heart. There are no drugs that prevent organ damage caused by these injuries, which ultimately leads to chronic heart failure, making ischemic heart disease the leading cause of death worldwide. Globally, 1 in 5 people develop heart failure, with annual healthcare costs of $108 B. Our team has discovered a new class of molecules, acid sensitive ion channels, that mediate cell death responses in the heart during ischemic injuries like heart attacks. This project will study the function of acid sensing channels using cell and genetic approaches. We will use innovative new drug discovery platforms to find new peptides and small molecules that inhibit acid channel activity. Finally, the project will use disease modelling in stem cells and animals to evaluate the implications of manipulating these channels using genetic or pharmacological approaches to study the implications in models of myocardial infarction. The candidate will benefit from background/expertise in cell biology and biochemistry. Collectively, this project will deliver new insights, tools, and molecules that underpin a key area of unmet clinical need in cardiovascular disease. The project will be supervised by experts in drug discovery, cell biology, and cardiovascular biology and includes opportunities for internships with industry partners such as Infensa Bioscience, a new spinout company from IMB developing cardiovascular therapeutics for heart disease.
*Development of peptide-based blood-brain barrier shuttles
Principal Advisor: A/Prof Markus Muttenthaler (m.muttenthaler@imb.uq.edu.au)
Associate Advisor: A/Prof. Johan Rosengren (SBMS, j.rosengren@uq.edu.au)
The blood-brain barrier controls the transfer of substances between the blood and the brain, protecting us from toxic compounds while allowing the transfer of nutrients and other beneficial molecules. This project aims to discover new venom peptides capable of crossing the blood-brain barrier and to develop non-toxic peptide-based brain delivery systems. It addresses long-standing challenges and knowledge gaps in the delivery of macromolecules across biological barriers. The project will involve cell culture, blood-brain barrier assays, proteomics, peptide chemistry, NMR structure determination, and molecular biology and pharmacology. The candidate should have a degree in biochemistry, pharmacology or cell biology, good hands-on laboratory skills and strong ambition and work ethics. Expected outcomes include an improved understanding of the strategies nature exploits to reach targets in the brain, mechanistic pathways to cross biological membranes, and innovative discovery and chemistry strategies to advance fundamental research across the chemical and biological sciences.
*Qualifies for the Global Challenges Scholarship.
Development of venom-derived blood-brain barrier shuttles
Principal Advisor: A/Prof Markus Muttenthaler (IMB)
Associate Advisor: A/Prof Johan Rosengren (UQ School of Biomedical Sciences)
The blood-brain barrier controls the transfer of substances between the blood and the brain, protecting us from toxic compounds while allowing the transfer of nutrients and other beneficial molecules. This project aims to discover new venom peptides capable of crossing the blood-brain barrier and to develop non-toxic peptide-based brain delivery systems. It addresses long-standing challenges and knowledge gaps in the delivery of macromolecules across biological barriers. The project will involve cell culture, blood-brain barrier assays, proteomics, peptide chemistry, NMR structure determination, and molecular biology and pharmacology. The candidate should have a degree in biochemistry, pharmacology or cell biology, good hands-on laboratory skills and strong ambition and work ethics. Expected outcomes include an improved understanding of the strategies nature exploits to reach targets in the brain, mechanistic pathways to cross biological membranes, and innovative discovery and chemistry strategies to advance fundamental research across the chemical and biological sciences.
*Exploring Australian Microbes for Next-Generation Medicines through Soils for Science (S4S)
Principal Advisor: Dr Zeinab Khalil (z.khalil@uq.edu.au)
Associate Advisor: Dr Angela Salim (a.salim@imb.uq.edu.au), Professor Rob Capon (r.capon@imb.uq.edu.au) and A/Prof Loic Yengo (l.yengo@imb.uq.edu.au)
Microbes have been a new promising source of modern medicines, including antibiotics (e.g. penicillin) and immunosuppressants (e.g. sirolimus) and well as agents to treat cancer (e.g. adriamycin) and cardiovascular (e.g. statins) disease, as well as many more. Recent advances in genomics offer the prospect of exciting new approaches to discovering the next generation of medicines hidden within the Australian microbiome.
To this end in 2020 we launched Soils for Science (S4S) as an Australia wide citizen science initiative, designed to engage the public, to collect 10's of thousands of soil samples from backyards across the nation, from which we will isolate 100's thousands of unique Australian microbes.
This project will annotate the S4S microbe library to prioritize those that are genetically and chemically unique. These will be subjected to cultivation profiling, and fermentation, followed by chemical analysis to isolate, identify and evaluate new classes of chemical diversity.
The successful candidate will join a multi-disciplinary team where, supported by microbiological and genomic sciences, they will gain skills and experience in analytical, spectroscopic and medicinal chemistry – to inform and inspire the discovery of future medicines.
Applicants must have a strong background with outstanding grades in organic chemistry, and with an interest in learning multidisciplinary biosciences.
*Qualifies for the Global Challenges Scholarship.
*Fine-tuning the application of peptide-based antimalarial drugs through understanding their mechanism of action
Principal Advisor: Dr Nicole Lawrence (n.lawrence@uq.edu.au)
Associate Advisor: Professor Denise Doolan (d.doolan@imb.uq.edu.au) and Professor David Craik (d.craik@imb.uq.edu.au)
Malaria is a disease caused by Plasmodium parasites. The disease kills half a million people every year and the parasites rapidly evolve resistance to new drugs. Developing new drugs with different ways of killing the parasites is important for staying ahead of the disease progression. We have developed peptide-based drugs that target red blood cells infected with malaria parasites. The peptides are safe and selective and are also less likely to result in the parasites developing drug resistance compared to existing small molecule drugs.
We are seeking a motivated PhD student to join our discovery team and contribute valuable knowledge required for developing lead peptides into new treatments for malaria.
The overall aims of the PhD project are:
1. Undertake genetic studies to understand how lead peptides affect malaria parasites at transcription and protein expression levels
2. Explore whether lead peptides have immune modulatory properties in animals
3. Identify combination treatment options by combining peptides with existing antimalarial drugs that have different mechanisms of killing parasites
*Qualifies for the Global Challenges Scholarship.
Investigating the role and therapeutic potential of the oxytocin receptor in prostate cancer
Principal Advisor: A/Prof Markus Muttenthaler
Associate Advisor: A/Prof. Jyotsna Batra (QUT; jyotsna.batra@qut.edu.au)
Prostate cancer is the second most frequent malignancy in men worldwide, causing over 375,000 deaths a year. When primary treatments fail, disease progression inevitably occurs, resulting in more aggressive subtypes with high mortality. This project focuses on the oxytocin/oxytocin receptor (OT/OTR) signalling system as a potential new drug target and biomarker to improve prostate cancer management and patient survival. Anticipated outcomes include a better understanding of OT/OTR’s role in prostate cancer and new therapeutic leads for an alternative treatment strategy.
The candidate should have a degree in biochemistry, pharmacology or cell biology, good hands-on laboratory skills, some bioinformatics skills (e.g., ability to implement statistical tests in R/Python and program scripts to automate analyses) and strong ambition and work ethics. The candidate will be involved in genetic/bioinformatic analysis, cancer cell signalling assays, chemical synthesis of OT ligands, GPCR pharmacology and characterisation of therapeutic leads in prostate cancer models.
Investigating the therapeutic potential of the trefoil factor family for treating gastrointestinal disorders.
Principal Advisor: A/Prof Markus Muttenthaler (m.muttenthaler@imb.uq.edu.au)
Associate Advisor: A/Prof Johan Rosengren (UQ School of Biomedical Sciences; j.rosengren@uq.edu.au)
Inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS) affect 10–15% of the population, having a substantial socio-economic impact on our society. The aetiology of these disorders remains unclear, and treatments focus primarily on symptoms rather than the underlying causes.
Our research group is pursuing innovative therapeutic strategies targeting gastrointestinal wound healing and protection to reduce and prevent such chronic gastrointestinal disorders. This project focuses on the trefoil factor family, an intriguing class of endogenous gut peptides and key regulators for gastrointestinal homeostasis and protection. The project will focus on the chemical synthesis of the individual members and molecular probe and therapeutic lead development to advance our understanding of their mechanism of action and explore the therapeutic potential of these peptides for treating or preventing gastrointestinal disorders.
The candidate should have a degree in chemistry, biochemistry, pharmacology or cell biology, good hands-on laboratory skills, and strong ambition and work ethics. The candidate will be involved in solid-phase peptide synthesis, medicinal chemistry, mass spectrometry, structure-activity relationship studies, NMR, cell culture, wound healing assays, gut stability assays, cell signalling and receptor pharmacology.
*Mapping chemical diversity in Australian marine microbes
Principal Advisor: Dr Zeinab Khalil (z.khalil@uq.edu.au)
Associate Advisor: Dr Angela Salim (a.salim@imb.uq.edu.au), Professor Rob Capon (r.capon@imb.uq.edu.au) and Dr Mariusz Skwarczynski (SCMB)
There are multiple reasons why the discovery and development of new marine bioproducts is highly dependent on a quantitative understanding (mapping) of the chemical diversity intrinsic to different Australian marine biomass.
Firstly, the informed selection of marine biomass strains to support commercial production is greatly enhanced by knowledge of the yield, structures and diversity of small molecule and peptide bioactives – especially where these are the active agents critical to product properties (ie human health immunomodulatory, anti-infective, cardioprotective, neuroprotective and antioxidants; animal health antiparasitics; crop protection fungicides, herbicides and insecticides; livestock/crop productivity grow promoters; and/or new fine chemical pigments or flavouring agents).
Secondly, knowledge of chemical diversity and bioactives can significantly advance the design of optimal methods for production, harvest, handling, biorefining, biomanufacturer and product formulation, inclusive of quality control to monitor bioactive recovery, stability and content at each stage of the production cycle.
Thirdly, knowledge of chemical diversity can be used to improve the utilisation of biomass, and increase commercial returns, by identifying additional product classes from a single biomass. For example, analysis of biorefinery fractions after recovery of a primary marine bioproduct (ie omega-3-fatty acids or fucoidan) could reveal new product classes – with application inclusive of new functional foods and feeds, nutriceuticals, therapeutics, livestock and crop agrochemicals, and more.
This project seeks to develop advanced and optimised methods in UPLC-QTOF-MS/MS molecular networking, to rapidly, cost effectively, reproducibly and quantitatively map the small molecule and peptide chemical diversity of taxonomically and geographically diverse Australian marine microbes and microalgae, including fresh and processed biomass, biorefinery fractions and outputs, and formulated marine bioproducts – to advance the discovery and development of valuable new marine bioproducts.
The successful candidate will join a multi-disciplinary team where, supported by microbiological and genomic sciences, they will gain skills and experience in analytical, spectroscopic and medicinal chemistry – to inform and inspire the discovery of future marine bioproducts.
Applicants must have a strong background with outstanding grades in organic chemistry, and with an interest in learning multidisciplinary biosciences.
*Qualifies for the Global Challenges Scholarship.
*Medicinal chemistry strategies to remove bacterial biofilms associated with gastrointestinal disorders
Principal Advisor: A/Prof Markus Muttenthaler (m.muttenthaler@imb.uq.edu.au)
Associate Advisor: Professor Mark Blaskovich (m.blaskovich@imb.uq.edu.au)
Gastrointestinal disorders such as irritable bowel disorders (IBS) and inflammatory bowel diseases (IBD) affect 10–15% of the population, reduce the quality of life of millions of individuals, and result in substantial socioeconomic costs. Recently, we revealed a high prevalence of macroscopically visible bacterial biofilms in the gastrointestinal tracts of IBD and IBS patients, linking these biofilms to a dysbiosis of the microbiome and the pathologies. Using patient-derived biofilm-producing bacterial strains, we established biofilm bioassays and identified leads capable of removing these biofilms.
This project pursues cutting-edge medicinal chemistry strategies to advance various lead molecules towards drug candidates and enhance their therapeutic window and biofilm-specificity. Techniques that will be acquired include: solid-phase peptide synthesis, organic chemistry, medicinal chemistry, high-performance liquid chromatography, mass spectrometry, proteomics, nuclear magnetic resonance spectroscopy, gut stability assays, and antimicrobial and biofilm assays.
The candidate should have a degree in chemistry, biochemistry or pharmacology, good hands-on laboratory skills, and a desire to drive the project. The candidate will be involved in solid-phase peptide synthesis, medicinal chemistry, mass spectrometry, structure-activity relationship studies, gut stability assays, and antimicrobial, antibiofilm and cytotoxicity assays.
Molecular mechanisms of jellyfish envenomation
Principal Advisor: Dr Andrew Walker (IMB)
Associate Advisor: A/Prof Nathan Palpant (IMB)
Jellyfish cause some of the most serious envenomation syndromes of all animals, responsible for >77 deaths in Australia to date and many more around the world. Two jellyfish of interest are the box jellyfish Chironex fleckeri, whose venom targets the heart to kill in as little as two minutes; and its much smaller relative the Irukandji jellyfish Carukia barnesi, envenomation by which causes a long-lasting and painful ordeal. Jellyfish also represent an ancient group of venomous animals with unique biology different from all other venomous animals. Despite this, little is known about jellyfish toxins, how they work, or how we might design therapeutics or novel treatments to ameliorate their effects. This project would involve combining state-of-the-art techniques to isolate and characterise jellyfish toxins, test them using a range of bioassays, and assess possible agents to protect from their harmful effects.
New chemical space as a source of new drug leads
Principal Advisor: Dr Zeinab Khalil (IMB)
Associate Advisor: Prof Ian Henderson (IMB); Prof Rob Capon (IMB)
Microbes have been a new promising source of modern medicines, including antibiotics (e.g. penicillin) and immunosuppressants (e.g. sirolimus) and well as agents to treat cancer (e.g. adriamycin) and cardiovascular (e.g. statins) disease, as well as many more. Recent advances in genomics offer the prospect of exciting new approaches to discovering the next generation of medicines hidden within the Australian microbiome.
To this end in 2020 we launched Soils for Science (S4S) as an Australia wide citizen science initiative, designed to engage the public, to collect 10's of thousands of soil samples from backyards across the nation, from which we will isolate 100's thousands of unique Australian microbes.
This project will annotate the S4S microbe library to prioritize those that are genetically and chemically unique. These will be subjected to cultivation profiling, and fermentation, followed by chemical analysis to isolate, identify and evaluate new classes of chemical diversity.
The successful candidate will join a multi-disciplinary team where, supported by microbiological and genomic sciences, they will gain skills and experience in analytical, spectroscopic and medicinal chemistry – to inform and inspire the discovery of future medicines.
Applicants must have a strong background with outstanding grades in organic chemistry, and with an interest in learning multidisciplinary biosciences.
*Targeting the oxytocin receptor for breast tumour reduction
Principal Advisor: A/Prof Markus Muttenthaler (m.muttenthaler@imb.uq.edu.au)
Associate Advisor: A/Prof Loic Yengo (l.yengo@imb.uq.edu.au)
Over half a million women die from breast cancer annually (>3,000 in Australia), affecting one in eight women. It is therefore important to pursue new drug targets to improve therapy and patient survival. The oxytocin/oxytocin receptor (OT/OTR) signalling system plays a key role in childbirth, breastfeeding, mother-child bonding and social behaviour. It is also involved in breast cancer, where it modulates tumour growth, including subtypes such as triple-negative breast cancer that remain difficult to treat.
This project will investigate OT/OTR’s role in tumour growth and metastasis and assess its therapeutic potential in breast cancer management. It will focus on the OTR-specific tumour growth and metastasis pathways and on developing therapeutic leads derived from nature to reduce tumour growth. Anticipated outcomes include a better understanding of OT/OTR’s role in breast cancer and new therapeutic leads for an alternative treatment strategy.
The candidate should have a degree in biochemistry, pharmacology or cell biology, good hands-on laboratory skills, some bioinformatics skills (e.g., ability to implement statistical tests in R/Python and program scripts to automate analyses) and strong ambition and work ethics. The candidate will be involved in genetic/bioinformatic analysis, cancer cell signalling assays, chemical synthesis of OT ligands, GPCR pharmacology and characterisation of therapeutic leads in breast cancer models.
*Qualifies for the Global Challenges Scholarship.
The discovery and development of highly stable venom-derived peptide drug leads
Principal Advisor: A/Prof Markus Muttenthaler (IMB)
Associate Advisor: A/Prof Johan Rosengren (UQ School of Biomedical Sciences)
Venoms comprise a highly complex cocktail of bioactive peptides evolved to paralyse prey and defend against predators. The homology of prey and predator receptors to human receptors renders many of these venom peptides also active on human receptors. Venoms have therefore become a rich source for new neurological tools and therapeutic leads with many translational opportunities.
This project covers the discovery, chemical synthesis, and structure-activity relationship studies of venom peptides, with a specific focus on gastrointestinal stability and drug targets in the gut. Venom peptides are known for their disulfide-rich frameworks supporting secondary structural motifs not only important for high potency and selectivity but also for improved metabolic stability. While primarily studied for their therapeutic potential as injectables, this project will break new ground by investigating evolutionarily optimised sequences and structures that can even withstand gastrointestinal digestions, thereby providing new insights for the development of oral peptide therapeutics targeting receptors within the gut. These therapeutic leads will have enormous potential for the prevention or treatment of gastrointestinal disorders or chronic abdominal pain.
The candidate should have a degree in synthetic chemistry, biochemistry or pharmacology, good hands-on laboratory skills, and strong ambition and work ethics. The candidate will be involved in solid phase peptide synthesis, medicinal chemistry, mass spectrometry, NMR structure determination, CD studies, structure-activity relationship studies, gut stability assays, and receptor pharmacology.
The physiological role and therapeutic potential of gut peptides modulating appetite
Principal Advisor: A/Prof Markus Muttenthaler (m.muttenthaler@imb.uq.edu.au)
Associate Advisor: Dr. Sebastian Furness (SBMS, s.furness@uq.edu.au)
The advent of highly processed, calorie-rich foods in combination with increasingly sedentary lifestyles has seen a rapid rise in overweight and obesity. 60–80% of populations in developed countries are overweight or obese, and over three million deaths each year are attributed to a high body mass index. Obesity is also a risk factor for diabetes, hypertension, cardiovascular disease, kidney disease and cancer. This has a clear impact on life expectancy, with predictions that this generation will be the first to have a shorter life expectancy than the last. Despite this enormous socio-economic impact, treatment options are limited.
Our research groups are interested in the role of the gut peptides GLP-1 and CCK in regulating appetite and satiety. A subset of GLP-1 mimetics are already successful treatments for obesity; however, compliance is low as they are injectables. The project will focus on the development of orally active mimetics. The project will also develop molecular probes to facilitate the study of the GLP1 and CCK1 receptors in the context of appetite regulation across the gut-brain axis.
The candidate should have a degree in chemistry, biochemistry or pharmacology, good hands-on laboratory skills, and a desire to drive the project. The candidate will be involved in solid phase peptide synthesis, medicinal chemistry, mass spectrometry, structure-activity relationship studies, cell culture, gut stability assays, cell signalling and receptor pharmacology.
The therapeutic potential of the trefoil factor family in chronic gastrointestinal disorders
Principal Advisor: A/Prof Markus Muttenthaler (IMB)
Associate Advisor: Prof Alpha Yap (IMB)
Inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS) affect 10–15% of the Western population, having a substantial socio-economic impact on our society. The aetiology of these disorders remains unclear, and treatments focus primarily on symptoms rather than the underlying causes.
Our research group is pursuing innovative therapeutic strategies targeting gastrointestinal wound healing and protection to reduce and prevent such chronic gastrointestinal disorders. This project focuses on the trefoil factor family, an intriguing class of endogenous gut peptides and key regulators for gastrointestinal homeostasis and protection. The project will focus on the chemical synthesis of the individual members and molecular probe and therapeutic lead development to advance our understanding of their mechanism of action and explore the therapeutic potential of these peptides for treating or preventing gastrointestinal disorders.
The candidate should have a degree in chemistry, biochemistry, pharmacology or cell biology, good hands-on laboratory skills, and strong ambition and work ethics. The candidate will be involved in solid phase peptide synthesis, medicinal chemistry, mass spectrometry, structure-activity relationship studies, NMR, cell culture, wound healing assays, gut stability assays, cell signalling and receptor pharmacology.
Towards the sustainable discovery and development of new antibiotics
Principal Advisor: Dr Zeinab Khalil (z.khalil@uq.edu.au)
Associate Advisor: Dr Angela Salim (a.salim@imb.uq.edu.au), Professor Rob Capon (r.capon@imb.uq.edu.au) and Professor Waldemar Vollmer (w.vollmer@imb.uq.edu.au)
The worldwide emergence and relentless escalation of antibiotic drug resistance (i.e. methicillin-resistant Staphylococcus aureus) have demanded ongoing commitment over decades to discovering new antimicrobial weapons.1 Yet, even with the widespread acceptance of the need for new antibiotics in both the scientific community and the public at large, an urgent need for new approaches remains. Fortunately, microorganisms continue to produce their own wealth of structurally diverse and highly specialised metabolites, each with a remarkable range of biological activities that in themselves could present the next antibiotic breakthrough.
Microbial genomes are rich in silent biosynthetic gene clusters (BGCs), encoding for defensive agents (i.e. antibiotics) that fail to express in standard laboratory monoculture conditions, presumably due to the paucity of environmental cues. Nitric oxide (NO) is well known for its regulatory role in mammalian and plant biology, little is known about its role in regulating microbial silent BGCs. We revealed Nitric Oxide Mediated Transcriptional Activation (NOMETA) as a potentially cost-effective & rapid approach for an in situ (i.e. non-genome mining) approach to accessing the valuable chemistry encoded within microbial silent BGCs.
This project will deliver two key solutions to the major problem of AMR: (i) develop an innovative method that applies NO to activate the transcription of microbial silent BGCs to access new defensive agents capable of informing the development of new antibiotic classes, and (ii) apply new genomic and metabolomics data mining technologies for microbes identified in our Soils for Science citizen science program to identify additional antibiotics for future drug development.
Join our collaborative team as we explore the frontiers of analytical, spectroscopic, and medicinal chemistry, guided by the expertise of microbiological and genomic sciences. Together, we are on the verge of unveiling the mysteries of nature, paving the way for groundbreaking discoveries in the antibiotic drug discovery.
*Understanding the molecular structures of proteins involved in rare disease
Principal Advisor: Dr Rosemary Cater (r.cater@uq.edu.au)
Associate Advisor: Dr Brett Collins (b.collins@imb.uq.edu.au)
Rare diseases are often caused by genetic mutations that disrupt protein function. In some cases, we already understand the three-dimensional structure and functional role of these proteins in healthy individuals. However, unfortunately, for some rare diseases, we lack this knowledge. This lack of information prevents us from understanding how mutations within the protein can lead to malfunction and disease onset, which in turn prevents us from understanding the disease and how to treat it. This project will employ biochemical techniques, structural biology (cryo-EM), and computational approaches to understand the normal 3D structure and role of proteins implicated in rare diseases. By elucidating these aspects, we will provide critical insights for the development of drugs to treat these rare diseases.
*Qualifies for the Global Challenges Scholarship.
*Unveiling Potential Drug Candidates for Inflammatory Bowel Disease within the Rich Tapestry of the Australian Microbiome
rincipal Advisor: Dr Zeinab Khalil (z.khalil@uq.edu.au)
Associate Advisor: Dr Angela Salim (a.salim@imb.uq.edu.au), Professor Rob Capon (r.capon@imb.uq.edu.au) and Dr Rabina Giri (Mater Health)
Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract, encompassing disorders like Crohn's disease and ulcerative colitis. With existing treatments often falling short, there's a growing need for innovative solutions.
In 2020, we initiated the Soils for Science (S4S) project, a nationwide citizen science endeavor collecting soil samples from backyards across Australia. Within this diverse microbial landscape, we seek answers to IBD.
Our mission involves annotating the S4S microbe library, prioritizing genetically and chemically unique microbes. Through cultivation profiling and fermentation, we aim to harness the untapped potential of these microbes for drug discovery. The ensuing chemical analysis will isolate, identify, and evaluate new compounds with the potential to revolutionize IBD treatment.
Join our multidisciplinary team and dive into the world of analytical, spectroscopic, and medicinal chemistry, guided by microbiological and genomic sciences. Together, we are poised to unlock nature's secrets and pave the way for groundbreaking treatments for Inflammatory Bowel Disease.
*Qualifies for the Global Challenges Scholarship.
Using transposon sequencing to probe whole cell protein-protein interactions inside the bacterial cell
Principal Advisor: Dr Emily Goodall (IMB)
Associate Advisor: Prof Ben Hankerman (IMB); Prof Ian Henderson (IMB)
Friend or Foe, bacteria are powerhouses at the centre of many important biotechnological processes, but also the disease-causing agents of many infectious diseases. Understanding the fundamental processes of a bacterial cell is key to understanding (1) how to harness these organisms for biotechnological gain and (2) how to target them in the treatment of an infection. Using the model organism, Escherichia coli, we aim to develop a method for identifying protein-protein interactions in a high throughput format. The methodology developed in this project will enable total proteome screening and has implications for studying both fundamental cell physiology as well as the potential for studying protein-drug interactions in vivo. After development, the technology will be validated by screening for chemical inhibitors of protein-protein interactions.
Venom-derived drugs for targeting ion channels involved in genetic epilepsies
Principal Advisor: Prof Glenn King (IMB)
Associate Advisor: A/Prof Lata Vadlamudi (UQ Centre for Clinical Research)
There are more than 65 million people currently living with epilepsy, and more than 1/3 are resistant to anti-seizure medications (ASMs). For these latter patients, new efficacious ASMs are urgently required. This project will focus on development of biologic drugs for treatment of genetic epilepsies caused by aberrant expression of a voltage-gated ion channel. We are specifically interested in: (i) Dravet syndrome, which is caused by aberrant function of the voltage-gated sodium channel Nav1.1, and (ii) KCNH1 epilepsy, caused by gain-of-function mutations in the voltage-gated potassium channel Kv10.1, which was first described here at the Institute for Molecular Bioscience. This project brings together the expertise of the King lab in venoms-based peptide-drug discovery and development, and the clinical expertise of Prof. Vadlamudi in treatment of genetic epilepsies. Lead compounds will be isolated from arthropod venoms, the best known source of ion channel modulators. Prof. King’s lab has access to the largest collection of arthropod venoms in the world (>500 species). Lead compounds will be tested in brain organoids produced from patient-derived stem cells as well as in vivo rodent models of Dravet syndrome and KCNH1 epilepsy.
Venom-derived ion channel inhibitors as novel neuroprotective drugs for neurodegenerative diseases
Principal Advisor: Dr Fernanda C Cardoso (IMB)
Associate Advisor: Dr Jean Giacomotto (QBI/Griffith); Prof Glenn King (IMB)
Neurodegenerative diseases are caused by progressive loss of neurons, leading to dementia, motor dysfunction, paralysis, and death. Investigation of ion channels in central neurons unravelled clusters of voltage-gated ion channel subtypes playing a key pathological role in the pre-symptomatic stages of neurodegenerative diseases. Venoms are an exceptional source of peptides modulating ion channels with higher potency and selectivity than poorly efficacious drugs used in the treatment of neurodegeneration.
This project involves systematically interrogating venoms using computational approaches, high throughput in vitro and in vivo screens, venomics and pharmacology to discover venom peptides that selectively modulate ion channels in central neurons and therefore have the potential to prevent central neurodegeneration.
This is a multidisciplinary project in drug discovery utilizing venoms and other natural repertoires as main sources of bio-active molecules. PhD scholars will develop skills in computational biology, manual and automated whole-cell patch clamp electrophysiology, ex vivo tissue electrophysiology, in vivo screen in zebrafish, high performance liquid chromatography, mass spectrometry, recombinant expression, peptide synthesis, amongst other state-of-the-art methods and techniques. Students will author papers and be involved in writing and preparation of figures for research publications from their work.
Venom-derived peptides as novel analgesic leads
Principal Advisor: Prof Irina Vetter IMB)
Associate Advisor: Dr Richard Clark (UQ School of Biomedical Sciences)
Voltage-gated sodium channels are well-validated analgesic targets, with loss-of-function mutations leading to an inability to sense pain, but otherwise normal physiology and sensations. However, efforts to mirror these genetic phenotypes with small molecule inhibitors have highlighted that both selectivity over ion channel subtypes and mechanism of action are key considerations for the development of safe and effective analgesics.
This project will leverage the exquisite potency and selectivity of peptide sodium channel modulators from venoms for the rational development of novel, safe and effective molecules with analgesic activity.
Students will gain experience with peptide synthesis, patch-clamp electrophysiology, sensory neuron culture, microscopy and in vivo behavioural assays to tackle the global problem of unrelieved chronic pain with innovative molecules targeting peripheral sensory neuron function.
*Venom-derived peptides to study heart function and treat cardiovascular disease
Principal Advisor: A/Prof Markus Muttenthaler (m.muttenthaler@imb.uq.edu.au)
Associate Advisor: A/Prof Nathan Palpant (n.palpant@uq.edu.au)
Cardiovascular disease is the leading cause of death in the world. Although therapies have improved, mortality remains high, and 1 in 5 people develop heart failure, resulting in global annual healthcare costs of $108 billion. Innovative solutions are therefore required to develop new therapies for heart disease.
Venoms comprise a complex cocktail of bioactive peptides that target many human receptors and are therefore a rich source of new pharmacological tools and therapeutic leads. This project focuses on identifying and developing such new tools and leads with interesting functions on the human heart.
Techniques will include venom-heart-function screens, tissue culture, proteomics, chemical synthesis and structure-activity relationship studies. Identified compounds will support the study of heart function and might lead to innovations in the prevention or treatment of cardiovascular disorders.
The candidate should have a degree in biochemistry, pharmacology and/or cell biology, good hands-on laboratory skills, and strong ambition and work ethics.
*Qualifies for the Global Challenges Scholarship.