Centre for Superbug Solutions - Project's List
Boosting innate immune defence to combat antibiotic-resistant bacterial infections
Principal Advisor: Prof Matt Sweet (IMB)
Associate Advisor: Prof Mark Schembri (IMB)
For bacterial pathogens to colonise the host and cause disease, they must first overcome frontline defence of the innate immune system. Innate immune cells such as macrophages engage a suite of direct antimicrobial responses to destroy engulfed bacteria, including free radical attack, lysosomal degradation, nutrient starvation, metal ion poisoning, and lipid droplet-mediated delivery of antimicrobial proteins. A detailed understanding of such pathways can provide opportunities to manipulate macrophage functions to combat antibiotic-resistant bacterial infections. This project will explore the regulation of specific macrophage antimicrobial responses, with the goal of manipulating the functions of these cells to combat infections caused by uropathogenic E. coli, a major cause of urinary tract infections and sepsis.
*Chemical embedding in artificial intelligence models
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.
*Qualifies for the Global Challenges Scholarship.
*Developing ionobiotics for the targeted treatment of multi-drug resistant bacteria
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.
*Qualifies for the Global Challenges Scholarship.
Genetics of biofilms
Principal Advisor: Prof Mark Schembri (m.schembri@uq.edu.au)
Associate Advisors: Dr Nhu Nguyen (kn.nguyen@uq.edu.au) and Dr Zack Lian (IMB; z.lian@uq.edu.au)
Biofilms are surface-attached clusters of bacteria encased in an extracellular matrix and are significantly associated with increased antibiotic resistance. This project will apply molecular microbiology methods to understand the structure, function and regulation of biofilms produced by uropathogenic E. coli that cause urinary tract infections, and investigate new strategies to disrupt biofilms. The project will build skills in cutting edge genetic screens, molecular microbiology, genome sequencing, bioinformatics, microscopy, imaging and animal infection models. Students with an interest in microbiology, bacterial pathogenesis and antibiotic resistance are encouraged to apply.
How antibiotic resistant bacteria cause urinary tract infection
Principal Advisor: Prof Mark Schembri (IMB)
Associate Advisor: Prof Matt Sweet (IMB)
Urinary tract infections (UTIs) are one of the most common infectious diseases, with a global annual incidence of ~175M cases. UTI is also a major precursor to sepsis, which affects ~50M 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. The last decade has seen an unprecedented rise in antibiotic resistance among UPEC, resulting in high rates of treatment failure and mounting pressure on healthcare systems. This project will explore how UPEC cause disease and become resistant to antibiotics, with a goal to identify new approaches to treat and prevent infection.
How bacteria cause severe life-threatening infections in infants
Principal Advisor: Prof Mark Schembri (IMB)
Associate Advisor: A/Prof Adam Irwin (UQ Centre for Clinical Research)
Neonatal meningitis is a devasting disease with high rates of mortality and neurological sequelae. Escherichia coli is the second most common cause of neonatal meningitis and the most common cause of meningitis in preterm neonates. Despite this, we have limited knowledge about the global epidemiology of E. coli that cause neonatal meningitis, genomic relationships between different strains, and mechanisms that enable E. coli to cause severe infection in new-born infants. This project will identify and characterise common genomic features of E. coli that cause neonatal meningitis, and employ molecular microbiology methods in conjunction with animal models to understand disease pathogenesis and antibiotic resistance. Our goal is to develop new diagnostic and therapeutic interventions to prevent this life-threatening disease.
How bacteria fortify their cell envelope under stress
Principal Advisor: Professor Waldemar Vollmer (w.vollmer@uq.edu.au)
Associate Advisor: Prof Mark Schembri (m.schembri@uq.edu.au)
Gram-negative bacteria use some of their most abundant cellular proteins connect the outer membrane with the underlying cell wall (peptidoglycan) layer and this tight connection protects the cell from many toxic molecules and even antibiotics. However, most of the known peptidoglycan-interacting proteins are poorly characterised and we lack a comprehensive inventory of these proteins and their functions in key pathogens. In this project, the PhD student will develop novel proteomics approaches to identify all peptidoglycan-bound proteins in important Gram-negative pathogens, and then identify peptidoglycan-interacting proteins that fortify the cell envelope when bacteria encounter host defence factors and antibiotics. In addition to state-of-the art molecular biology and high-throughput microbiology screening techniques, the student will use cell biology and biochemical methodologies to gain understanding of the cellular roles of new cell envelope proteins identified. The student will benefit from working in an outstanding research environment and in research groups with a strong expertise in bacterial cell envelope biology and pathogenicity. The expected outcomes will be important to develop new strategies to fight infections caused by antibiotic resistant bacteria.
*How E. coli cause urinary tract infections
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.
*Qualifies for the Global Challenges Scholarship.
How does innate immune signalling combat influenza in birds?
Principal Advisor: Dr Larisa Labzin (IMB)
Associate Advisor: A/Prof Kirsty Short (UQ School of Chemistry and Molecular Biosciences)
Emerging viruses such as Highly Pathogenic Avian Influenza, HPAIV and SARS-CoV-2 can cause deadly outbreaks that decimate wild and domestic animal populations or cause global pandemics. . Some species, particularly bats and wild birds, can carry these viruses with minimal disease, meaning they can easily spread viruses between farms, states and even countries. The immune response is the best protection against viral infection, yet in susceptible species (such as chickens and pigs), immune overactivation may cause collateral tissue damage, driving disease pathology. This PhD project will study how the immune systems of different species recognise viral infections. This research will determine if viral reservoir species (such as ducks and bats) mount a specific kind of immune response that allows them to tolerate viruses, which is distinct to susceptible species (such as chickens and pigs). This project will utilise cell biology, imaging, molecular cloning, and virology to identify new ways to prevent pandemic virus outbreaks and protect vulnerable species.
Molecular Immunology of Malaria
Principal Advisor: Prof Denise Doolan (IMB)
Associate Advisor: Prof Gabrielle Belz (Frazer Institute)
An opportunity exists for a PhD position in the molecular immunology of malaria. The focus of this project will be to apply cutting-edge technologies to understand the molecular basis of protective immunity to malaria. It will take advantage of controlled human infection models and as well as animal models to explore the mechanisms underlying protective immunity to malaria and immune responsiveness. Using a range of interdisciplinary approaches including immune profiling, transcriptomics, proteomics, and small molecule characterization, the project aims to define the critical cells and signalling pathways required for protective immunity against malaria. It is anticipated that this research will have broad application to a wide range of infectious and chronic diseases, with important implications for vaccination.
Subject areas: Immunology, Molecular immunology, Systems biology, Vaccinology, Malaria
Eligibility: Entry: Bachelor degree with Honours Class I (or equivalent via outstanding record of professional or research achievements). Experience/Background: laboratory-based experience in immunology, host-pathogen interactions, immune regulation and infectious diseases; excellent computer, communication, and organisational skills are required.
Novel assays for antibiotic discovery
Principal Advisor: Prof Waldemar Vollmer (IMB)
Associate Advisor: Mr Alun Jones (IMB); Prof Rob Capon (IMB)
The PhD project addresses the global burden of Antimicrobial Drug Resistance (AMR) by developing new assays for antibiotic discovery. The bacterial cell wall is targeted by some of our best antibiotics (e.g., beta-lactams, glycopeptides) and remains an attractive target for antibiotic drug discovery. Our group investigates the molecular mechanisms underpinning cell wall synthesis during growth and division of a bacterial cell. We pioneered the development of biochemical assays to monitor the activities and interactions of essential enzymes required for the synthesis of peptidoglycan, identified the first activators of peptidoglycan synthases and deciphered the activation mechanism. The PGR student will be trained in a wide range of molecular biology, (analytical) biochemistry and bacterial cell biology techniques and use these to develop innovative assay for key peptidoglycan enzymes that built and remodel the cell wall in pathogenic bacteria. The PGR student will then use the new assays to screen compound libraries to identify inhibitors. Hit compounds will be characterised by cellular and biochemical techniques and assessed for their potential to be developed into new antibiotics.
PET Imaging of Bacterial Infections
Principal Advisor: A/Prof Mark Blaskovich (IMB)
Associate Advisor: Prof Kristofer Thurecht (UQ Centre for Advanced Imaging); Dr Anthony Verdosa (IMB)
Infections caused by drug resistant bacteria pose a significant threat to global human health, with predicted annual mortality of 10 million by 2050. Most research is focused on developing better therapies, but improving diagnosis could quickly have substantial impact by reducing unnecessary antibiotic use and enhancing therapeutic efficacy. There is no current clinical technology capable of specifically identifying bacterial infections by imaging the site of a bacterial infection. Suspected chronic infections, such as endocarditis and prosthetic joint infections, are particularly difficult to accurately diagnose without invasive techniques. A whole-body imaging diagnostic that could simultaneously determine whether an infection was present and rapidly pinpoint the site of the infection, then monitor the efficacy of subsequent treatment, would directly inform targeted treatment, leading to substantial health and economic benefits. This project will extend our current research on fluorescent tracers that bind to the surface of bacteria with high specificity and selectivity. We will replace the fluorophore component of these tracers with radioisotope chelating ligands, creating new constructs suitable for positron emission tomography (PET) whole body imaging. These tracers will be tested both in vitro and in mice to demonstrate specific PET imaging of bacterial infections.
Systems immunology and multi-omics approaches to understand protective immunity to human malaria
Principal Advisor: Prof Denise Doolan (IMB)
Associate Advisor: Dr Carla Prioetti (IMB); A/Prof Jessica Mar (AIBN)
This PhD project aims to develop and apply computational approaches that integrate systems biology and molecular immunology to understand host-pathogen immunity and predict immune control of malaria. The project will utilise systems-based immunology and multi-omics approaches to profile the host immune response in controlled infection models of malaria at molecular, cellular, transcriptome and proteome-wide scale.
The overall aim will be to develop and apply omics-based technologies and computational tools, including network theory and machine learning, to integrate multiple high-dimensional datasets and reveal novel insights into host-pathogen immunity and predict immune responsiveness and parasite control. Modelling of large-scale existing datasets, including those generated by single-cell RNA-sequencing technologies, may also be a feature of this project. The opportunity to identify new knowledge and integrate this with experimental data produced by our laboratory will be instrumental to extending the impact of these bioinformatics analyses. This project will provide an opportunity to be at the forefront in cutting-edge technologies and advances in computational analysis of integrated high-dimensional omic data.
Eligibility:
Entry: BSc Honours Class I (or equivalent via outstanding record of professional or research achievements)
Experience/Background: Experience with programming languages, mathematics, statistics and/or background in immunology and molecular sciences, with an interest in integrating the fields of immunology and bioinformatics.
Excellent computer, communication, and organisational skills are required. Forward thinking, innovation and creativity are encouraged.
Targeting the membrane steps in bacterial cell wall synthesis for antibiotic drug discovery
Principal Advisor: Prof Waldemar Vollmer (IMB)
Associate Advisor: Mr Alun Jones (IMB); Prof Rob Capon (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. We study the key essential steps of cell wall synthesis at the cell membrane, 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 new assays to measure the activities of membrane-bound cell wall enzymes. The PGR student will then use the new assays in proof-of-principle studies to screen for new inhibitors. 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.
The application of metagenomics to clinical microbiology and infection control
Principal Advisor: Dr Brian Forde (b.forde@uq.edu.au)
Associate Advisors: Dr Patrick Harris (UQCCR, p.harris@uq.edu.au), Dr Kym Lowry (UQCCR, k.lowry@uq.edu.au)
Hospital-acquired infections (HAIs) present significant healthcare challenges globally, affecting patients in both developed and developing nations. In Australia alone, over 165,000 patients suffer from HAIs annually, with antimicrobial resistance (AMR) compounding the issue by limiting treatment options and worsening patient outcomes. Prospective whole-genome sequencing (WGS) has emerged as an optimal approach for rapidly identifying transmission of multi-drug resistant (MDR) bacteria. However, current surveillance methods primarily rely on culture-based isolation of specific pathogens, followed by detailed genomics characterisation of individuals, which is labour-intensive, prone to selection bias, and fails to provide insights into community dynamics and interactions between patients and the hospital environment. This project aims to pioneer an alternative approach: prospective metagenomic surveillance. By leveraging high-throughput metagenomics, this project seeks to profile overall community structure, characterise community dynamics, and identify and control pathogen transmission in clinical settings. The research will involve developing new workflows and pipelines to integrate metagenomic surveillance into routine clinical practice, thereby enhancing infection control strategies and patient care
Understanding antibiotic resistance
Principal Advisor: Prof Mark Schembri (m.schembri@uq.edu.au)
Associate Advisor: Dr Brian Forde (b.forde@uq.edu.au), Dr Patrick Harris (UQCCR; p.harris@uq.edu.au), Dr Minh-Duy Phan (IMB; m.phan1@uq.edu.au)
Antimicrobial resistance (AMR) is a major threat to global human health. In 2019 alone, there were an estimated 4.95 million deaths associated with bacterial AMR, with uropathogenic E. coli (UPEC) a leading pathogen associated with urinary tract infections, sepsis and high rates of antibiotic resistance. This project will use cutting edge genetic screens, molecular microbiology, genome sequencing and bioinformatics to understand how plasmids contribute to the spread of antibiotic resistance in UPEC. Students with an interest in microbiology, bacterial pathogenesis and antibiotic resistance are encouraged to apply.
Understanding the link between EBV and Multiple Sclerosis
Principal Advisor: Prof Denise Doolan (IMB)
Associate Advisor: Dr Carla Prioetti (IMB)
An opportunity exists for a PhD position in molecular immunology, where cutting-edge technologies will be applied to understand the molecular basis of the link between EBV and Multiple Sclerosis. Epstein-Barr virus (EBV) is the top identified causative agent of Multiple Sclerosis, but how this occurs is not known. This project aims to apply an innovative approach using proteome-wide screening of EBV to identify the subset of EBV proteins from the complete EBV proteome that triggers MS. It will compare responses in individuals with different stages of MS and apply sophisticated computational analytics to identify specific EBV proteins that predict MS disease. This EBV signature of MS could be translated into a clinic-friendly point-of-care test. If successful, this project could revolutionize the diagnosis and management of MS, providing patients with a quicker and more accurate diagnosis and enhanced quality of life.
Eligibility:
Entry: Bachelor degree with Honours Class I (or equivalent via outstanding record of professional or research achievements)
Experience/Background: laboratory-based experience in immunology, host-pathogen interactions, immune regulation and infectious diseases; excellent computer, communication, and organisational skills are required.
Understanding the role of lipids in inflammation and immune clearance of pathogens
Principal Advisor: Dr Jessica Rooke (IMB)
Associate Advisor: Prof Ian Henderson (IMB); Prof Matt Sweet (IMB)
Salmonella enterica is a broad host range pathogen that is distributed globally. Worryingly, S. enterica strains are becoming increasingly resistant to routinely used antibiotics, leading to the World Health Organisation classifying S. enterica as a high priority pathogen for which alternative treatments are desperately needed. By understanding how Salmonellainfects a host, novel therapies and vaccines can be designed to prevent disease. Recent evidence suggests that pathogen-lipid interactions are important for pathogens to survive in the host and that Salmonella has a unique, conserved lipase that is essential for these interactions. This project aims to establish the molecular mechanism by which Salmonella interacts with host lipids to enable evasion and manipulation of host immune responses. These investigations will provide novel insights into fundamental Salmonella biology and aid in the development of more effective strategies to treat Salmonella infections, such as novel drug targets and/or novel vaccine candidates.
Vaccine Engineering
Principal Advisor: Prof Denise Doolan (IMB)
Associate Advisor: Dr Carla Prioetti (IMB)
An opportunity exists for a PhD position in vaccine engineering. Vaccines are one of the most effective health care interventions but remain a challenge for many diseases, and in particular intracellular pathogens such as malaria where T cell responses are particularly desirable. We have been exploring novel approaches to rationally design an effective vaccine against challenging disease targets. By taking advantage of recent advances in genomic sequencing, proteomics, transcriptional profiling, and molecular immunology, we have discovered unique targets of T cell responses or antibody response. This project will test these antigens as vaccine candidates by assessing immunogenicity, protective capacity and biological function using different vaccine platforms. By designing an effective vaccine from genomic data, this project is expected to result in significance advances in vaccinology as well as immunology, with important public health outcomes.
Eligibility:
Entry: Bachelor degree with Honours Class I (or equivalent via outstanding record of professional or research achievements)
Experience/Background: laboratory-based experience in immunology, host-pathogen interactions, immune regulation and infectious diseases; excellent computer, communication, and organisational skills are required.