PhD GC Projects list

Principal Advisor: Dr Johannes Zuegg (j.zuegg@imb.uq.edu.au)

Associate Advisor: TBC

The embedding of chemical structures for deep learning network is currently limited to a few approaches that fail to represent the chemical properties in an efficient and comprehensive way. Especially for large language models the embedding of chemical information is limited to methods containing few chemical properties, or associated biological activities in the case of bioactive chemicals. The project will explore and develop embedding methods that can enrich chemical and biological properties, using chemical relevant transformations to provide enriched descriptors. The project will explore their application in predictive and generative models, able to generate new chemical structures with a desired biological activity. The project has thereby access to the existing large of the Community for Open Antimicrobial Drug Discovery (CO-ADD), which has collected the structures and biological activity of over 500,000 chemicals.

Principal Advisor: Dr Michael Healy (michael.healy@uq.edu.au)

Associate Advisor: Professor Brett Collins (b.collins@imb.uq.edu.au)

At the heart of neurodegeneration is the concept of proteostasis, the tight regulation of protein synthesis, transport, degradation, and recycling. Defective proteostasis results in the toxic accumulation of proteins and peptides such as amyloid β (Aβ) and phosphorylated tau. The major pathway that regulates proteostasis is the sorting and degradation of transmembrane proteins in the endolysosomal system, and associated autophagic and lysosomal destruction of toxic cytosolic molecules. Retromer is a trimeric protein complex that is a central player in regulating the endolysosomal system and is downregulated in the hippocampus of patients with Alzheimer’s disease. Molecules (termed molecular chaperones) that stabilise this complex increase Retromer levels in neurons and decrease levels of neurotoxic Aβ, however, to date no molecule has made it into the clinic. Here I will use our knowledge of fundamental Retromer biology to design a suite of ‘mini-protein’ molecular chaperones using revolutionary machine learning techniques (Alphafold, RFdiffusion) and test their ability to stabilise Retromer in vitro and reverse dysfunction in known cellular models of neurodegeneration. Unlike traditional drug screening approaches, these revolutionary techniques allow for the generation of novel protein backbones that bind to specified regions of a protein or protein complex. If successful, these molecular chaperones could represent novel therapeutics for the treatment of the underlying molecular pathology that is common in neurodegeneration.

Principal Advisor: Professor Mark Walker (mark.walker@uq.edu.au)

Associate Advisor: Dr David De Oliveira (d.deoliveira@uq.edu.au) and Proessor Maree Smith (SBMS; maree.smith@uq.edu.au)

Antimicrobial resistance (AMR) is a growing source of morbidity, mortality, and economic and health-care costs. The innovative use of ionophores to break antibiotic resistance in clinically relevant multidrug-resistant bacteria has paved a therapeutic pathway to investigate ionophores as direct-acting antibiotics. By utilising a validated drug development program, this project will define the utility of these promising new compounds by exploring their mode of action, the range of pathogens that can be treated, and their drug pharmacology profiles during infection. Ionophores represent a NEW-CLASS of antibiotics with broad-spectrum activity against a wide range of antimicrobial-resistant bacterial species. Our overarching goal is to expand the repertoire of effective antibiotic therapies available for AMR associated infections.

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. 

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.

Principal Advisor: Professor Jennifer Stow (j.stow@imb.uq.edu.au)

Associate Advisor: Professor Mark Schembri (m.schembri@uq.edu.au) and Professor Halina Rubinsztein-Dunlop (SMP; halina@physcics.uq.edu.au) 

The efficient delivery of drugs, vaccines, mRNAs and nanoparticles into human cells is still a major challenge for treating and preventing disease. Bugs, or bacteria, hold the key for penetrating our cells by hijacking endocytic, phagocytic and other trafficking pathways with their effector proteins. We can use these effectors too, to develop new methods for penetrating cancer cells and immune cells to improve drug delivery and to manipulate cell function and survival. Our bug-based effectors will be made, tagged and used for microscopy and live imaging of cells and for measuring biophysical properties of the cell membranes. We will explore effector-enhanced drug delivery and monitor disease processes in organoids and live tissues, in collaboration with microbiologists, physicists, immunologists and clinicians.

Principal Advisor: Professor Mark Schembri (m.schembri@uq.edu.au)

Associate Advisors: Professor Matthew Sweet (m.sweet@imb.uq.edu.au)

Urinary tract infections (UTIs) are one of the most common infectious diseases, with a global annual incidence of approximately 400 million cases. UTI is also a major precursor to sepsis, which affects about 50 million people worldwide each year, with a mortality rate of 20-40% in developed countries. Uropathogenic E. coli (UPEC) is the major cause of UTI and a leading cause of sepsis, and associated with high rates of antibiotic resistance. This project will explore how UPEC cause disease, with a goal to identify new approaches to treat and prevent infection. Students with an interest in microbiology, bacterial pathogenesis, animal infection models and antibiotic resistance are encouraged to apply.

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.

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.

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.

Principal Advisor: Professor Waldemar Vollmer (w.vollmer@imb.uq.edu.au)

Associate Advisors: Prof Rob Capon (IMB; r.capon@imb.uq.edu.au), Dr Zeinab Khalil (IMB; z.khalil@uq.edu.au), Dr Alun Jones (IMB) and Dr Rudi Sullivan (IMB)

There is an urgent need to develop new antibiotics to address the global challenge of antimicrobial drug resistance (AMR). The membrane steps in bacterial cell wall biogenesis include verified targets for antibiotics (e.g. daptomycin, teixobactin) which cause death and lysis of a bacterial cell. Our group works on the key essential membrane steps of cell wall synthesis, including the synthesis of lipid-linked precursor, the polymerisation of the cell wall and the recycling of the carrier lipid. The PGR student will receive extensive training in molecular biology, biochemistry and mass spectrometry techniques and develop novel, innovative assays to measure the activities of membrane-bound cell wall enzymes. The PGR student will then use these new assays to search for new inhibitors from Nature that inhibit the bacterial cell wall in the Australian Soil for Science microbe collection. The student will characterise the activity of hit molecules by bacterial cell biology techniques and assess their potential to be developed into new antibiotics.

References:

1. Egan et al. 2020. Regulation of peptidoglycan synthesis and remodelling. Nature Reviews Microbiology 18, 446–460.

2. Oluwole et al. 2022. Peptidoglycan biosynthesis is driven by lipid transfer along enzyme-substrate affinity gradients. Nature Communications 13:2278.

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.

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.

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.

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 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.

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.