Available Projects

Please note: We currently have a limited number of projects available to UK citizens only. Recruitment for the 2024 cohort will begin on Monday September 4th 2023 and the website will be updated accordingly. For more information on how to apply, please visit our “How to Apply for Students” page.

iCASE MRC23IIAREx Pagliara ‘Developing novel microfluidic platforms for antibiotic discovery’
MRC23IIARCa Eberl ‘Control of mucosal immunity and intestinal integrity by human gamma/delta T cells’
iCASE MRC23IIAREx Ballou ‘Looking for an Achilles Heel in the deadly fungi that cause Mucormycosis’

iCASE MRC23IIAREx Pagliara ‘Developing novel microfluidic platforms for antibiotic discovery’

Closing date: Friday 16^th June 2023 at 5pm
Eligibility: UK citizens only
Download project outline: Click here
Apply now: Click here

Supervisors

Lead Supervisor: Professor Stefano Pagliara, Exeter University, Living Systems Institute
Co-Supervisor: Professor Paul Race, Bristol University, Faculty of Life Sciences, School of Biochemistry
Co-Supervisor: Dr Fabrizio Pertusati, Cardiff University, College of Biomedical and Life Sciences, School of Pharmacy and Pharmaceutical Science
Co-Supervisor: Professor Sarah Harding, DSTL

Project Summary

Antimicrobial resistance is one of the most pressing public health challenges and threatens the ability to effectively fight infectious diseases, with around 10 million people predicted to die annually of infections by 2050. This project will tackle antimicrobial resistance by developing a biodiscovery pipeline for the isolation of bacteria and for the discovery of new antibiotic leads from previously uncultured microbes.

About the Project

Aim: This project will identify new molecules with antibiotic activity against multi-drug resistant bacterial pathogens. This is important and timely considering that antimicrobial resistance has claimed over 5 million deaths in 2019 alone.

Background: Due to the emergence of resistance, many of our most commonly used antibiotics have become ineffective at treating microbial infections especially those caused by multi-drug resistant ESKAPE pathogens, Burkholderia pseudomallei and Coxiella burnetii that are public health pathogens and potential biothreats. Thus, there is a pressing need to discover new antibiotic leads that are effective against multi-drug resistant bacteria. Natural products have long been the preeminent source of clinically viable antibiotics. However, there has not been a new, clinically viable class of antibiotic discovered since the 1980s. This is in part due to the inefficacy of antibiotic screening methods, which i) disproportionality target geographically redundant environments, and ii) rely on standard microbiological methods, leading to a high probability of compound rediscovery. This project will overcome these limitations by: i) employing a sampling approach that targets previously unexplored environmental niches, and ii) developing advanced screening approaches that better replicate natural environments.

Objective 1: To screen the Bristol Sponge Microbiome Collection using microfluidics. Using the Bristol Sponge Microbiome Collection, a unique repository of deep-sea microorganisms (Antibiotics 9:509, 2020), the student will screen for antimicrobial activity of substances exuded by these bacteria by employing a new microfluidics-microscopy approach (eLife 11, e74062, 2022). The main advantage of this platform is that it requires tiny operating volumes and thus will allow the student to detect activity from molecules that are not detected during standard susceptibility testing (Marine Drugs 19:105, 2021). The student will test the antimicrobial activity of identified substances against multi-drug resistant strains available in the supervisors’ laboratories including B. thailandensis, C. burnetii, A. baumannii and S. aureus. In order to establish the identity of new bioactive compounds from microorganisms displaying antimicrobial activity, the student will use liquid chromatography–mass spectrometry analysis (Marine Drugs 19:105, 2021).

Objective 2: To culture previously uncultured microorganisms using a novel biodiscovery pipeline. Using the isolation chip (iChip, Nature 517:455, 2015) available in our laboratories, the student will isolate microorganisms from samples of mud taken from the Yealm Estuary (that we have sampled during a previous studentship, MR/P016162/1). The main advantage of the iChip is that it utilises the specific environmental conditions found in the environment where microorganisms are naturally located and therefore favours the growth of previously uncultured microorganisms. The student will integrate the iChip device with our new microfluidics- microscopy assay for antibiotic susceptibility testing (eLife 11, e74062, 2022) that requires low input volumes. Microorganisms displaying antibiotic activity will be identified via 16S rRNA gene sequencing and phylogenetic analysis (Marine Drugs 19:105, 2021), whereas the identity of new bioactive compounds will be determined via liquid chromatography–mass spectrometry.

Objective 3: To synthesise and validate antibiotic analogues. Using medicinal chemistry, the student will synthesise analogues of new bioactive compounds discovered in objectives 1 and 2 and of compounds identified in our recent screening of the Bristol Sponge Microbiome Collection (Marine Drugs 19:105, 2021). Finally, using simple infection models, such as Galleria mellonella, the student will test the validity of these new bioactive compounds and analogues in vivo.

Eligibility

This studentship is open to applications from candidates who would be classified as UK citizens only.
All studentships are competitively awarded.
Applicants must have obtained, or be about to obtain, a UK degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences.
The DTP also welcomes students from non-medical backgrounds, especially in areas of computing, mathematics, and the physical sciences.
Academic qualifications are considered alongside any significant relevant non-academic experience.
If English is not your first language, you will need to meet the English language requirements of the university that will host your PhD by the start of the programme, Please refer to the Exeter University website here for further information on this.

Funding Notes

This GW4 BioMed2 MRC DTP iCASE studentship includes full tuition fees at UK level only, stipend at the minimum UKRI rate plus an iCASE stipend top up contribution of £2,500 per year from DSTL, a Research & Training Support Grant (RTSG) valued between £2-5k per year and a £300 annual travel and conference grant based on a 4-year, full-time studentship.

Throughout the duration of the studentship, there will be opportunities to apply to the Flexible Funding Supplement for additional support to engage in high-cost training opportunities.

How to apply and additional information

Please submit an application to the GW4 BioMed2 MRC DTP for an offer of funding. The closing date for application is Friday 16^th June 2023 at 5pm.

Candidates must be able to attend a virtual interview on 2^nd August 2023 and the successful candidate must be available to begin the PhD in Exeter on 1^st October 2023. The start date of this PhD cannot be deferred or delayed.

MRC23IIARCa Eberl ‘Control of mucosal immunity and intestinal integrity by human gamma/delta T cells’

Closing date: Friday 16^th June 2023 at 5pm
Eligibility: UK citizens only
Download project outline: Click here
Apply now: Click Here

Supervisors

Lead Supervisor: Professor Matthias Eberl, Cardiff University, BioMedical and Life Sciences, School of Medicine
Co-Supervisor: Dr Gareth Jones, Bristol University, Faculty of Life Sciences, School of Cellular and Molecular Medicine
Co-Supervisor: Dr Neil McCarthy, Barts and The London School of Medicine and Dentistry, Centre for Immunobiology, The Blizard Institute

Project Summary

γδ T cells are ‘unconventional’ lymphocytes that promote mucosal barrier defence and regulate immune responses to microbial infection. This PhD will use gene expression profiling, functional studies on cells from human blood and intestine, and organ chip-based / in vivo models to define how microbe-responsive γδ T cells control CD4+ T cell immunity and intestinal barrier function in health and inflammation.

About the Project

Background and significance. Human ‘unconventional’ lymphocytes are increasingly recognised to sense pathogens, influence recruitment and function of other immune cells, and help protect body tissues against infection. This project will study how γδ T cells in human blood and intestine control ‘conventional’ CD4+ T cell responses in health and disease. Polarisation of CD4+ T helper cells into Th1, Th2, Th17 and Treg cells is crucial for host defence against pathogens and tumours, but also for wound healing and resolution of inflammation. Better understanding of this process will therefore help inform the development of novel vaccines, treatments and diagnostics for a range of pathologies.

Preliminary work. Our data demonstrate a striking plasticity of human γδ T cells to modulate immunity at epithelial sites. A previous PhD student already identified γδ T cell signals that drive expression of the tissue-protective factors IL-22 and calprotectin in the human intestine (Tyler et al., 2017). More recent work shows that human γδ T cells can also induce anti-inflammatory CD4+ T cell responses marked by the expression of IL-10 (Eberl and McCarthy, unpublished).

Objective. To define the molecular mechanisms underlying CD4+ T cell polarisation by human γδ T cells during homeostasis and infection, and to identify ways to manipulate relevant pathways for future interventions

Aim 1. [Eberl, McCarthy] To study the potential of human γδ T cells to polarise primary CD4+ T cells towards distinct T helper subsets (Th1, Th2, Th17, Th22, Tfh, Treg).

Aim 2. [Eberl, Jones, McCarthy] To define the molecular signals that polarise CD4+ T cells towards distinct effector subsets by RNAseq profiling of activated human γδ T cells.

Aim 3. [McCarthy, Eberl] To validate polarising signals and manipulate pathways in cell culture, human intestinal tissues and gut-on-a-chip systems.

Aim 4. [Jones, Eberl] To investigate polarising pathways in mouse models: in vitro/in vivo T cell polarisation by signals identified in Aims 2+3 (with focus on CD4+ T-cells producing IL-10 or IL-22, and signalling via ICOS/ICOSL and CD30/CD30L).

Research Training. The student will receive expert training in core immunological techniques (cell culture, flow cytometry, cell sorting, ELISA, qPCR), organ-on-a-chip approaches, animal husbandry, gene profiling strategies (RNA sequencing) and bioinformatical analyses (Ingenuity Pathway Analysis).

Added-value. The student will work across disciplinary boundaries, by combining functional studies, bioinformatics approaches, analyses of clinical biopsies, organ chip systems, and in vivo models of inflammation. The student will take advantage of an established collaboration between Eberl and McCarthy, and benefit from extensive clinical expertise at The Blizard Institute at QMUL and cutting edge in vivo models at the University of Bristol.

Knowledge transfer and impact. The student will communicate their research to specialist and lay audiences through publications and presentations, and via engagement and outreach activities. Protocols and data will be freely exchanged between the three collaborating groups. Clinical implications of the findings will be discussed with the clinical team at Barts NHS Trust and with the Technology Transfer Office at Cardiff University.

Eligibility

This studentship is open to applications from candidates who would be classified as UK citizens only.
All studentships are competitively awarded.
Applicants must have obtained, or be about to obtain, a UK degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences.
The DTP also welcomes students from non-medical backgrounds, especially in areas of computing, mathematics, and the physical sciences.
Academic qualifications are considered alongside any significant relevant non-academic experience.
If English is not your first language, you will need to meet the English language requirements of the university that will host your PhD by the start of the programme, Please refer to the Cardiff university website here for further information on this.

Funding Notes

A GW4 BioMed2 MRC DTP studentship includes full tuition fees for both home and international students, a stipend at the minimum UKRI rate, a Research & Training Support Grant (RTSG) valued between £2-5k per year and a £300 annual travel and conference grant based on a 4-year, full-time studentship.

Part time study may also be available and funding arrangements will be adjusted pro-rata for part-time studentships. Throughout the duration of the studentship, there will be opportunities to apply to the Flexible Funding Supplement for additional support to engage in high-cost training opportunities.

How to apply and additional information

Please submit an application to the GW4 BioMed2 MRC DTP for an offer of funding. The closing date for application is Friday 16^th June 2023 at 5pm.

Candidates must be able to attend a virtual interview on 2^nd August 2023 and the successful candidate must be available to begin the PhD in Cardiff on 1^st October 2023. The start date of this PhD cannot be deferred or delayed.

iCASE MRC23IIAREx Ballou ‘Looking for an Achilles Heel in the deadly fungi that cause Mucormycosis’

Closing date: Friday 16^th June 2023 at 5pm
Eligibility: UK citizens only
Download project outline: Click here
Apply now: Click here

Supervisors

Lead Supervisor: Dr Elizabeth Ballou, University of Exeter, Faculty of Health and Life Sciences
Co-Supervisor: Dr Dora Corzo-Leon, University of Exeter, Faculty of Health and Life Sciences
Co-Supervisor: Professor Sarah Harding, DSTL, Porton Down
Co-Supervisor: Professor Simon Ward, Cardiff University, College of Biomedical and Life Sciences – Medicine Discovery Institute

Project Summary

Invasive infections by Mucorales fungi are life-threatening complications of severe blast trauma. Mucorales are resistant to most antifungals and cause devastating infections, yet are poorly understood. Mucorales are soil-swelling fungi and can host endosymbiotic bacteria that can influence fungal pathogenicity. We showed that removing endosymbionts can reduce fungal fitness. This project will identify compounds that target this partnership as an Achilles Heel as a strategy to mitigating fungal infections.

About the Project

Combat-related invasive fungal infections are life-threatening complications of severe blast trauma¹. They are often caused by soil-dwelling Mucorales fungi with high-level resistance to most currently available antifungal drugs. Yet devastating mucormycosis is understudied and poorly understood.

Mucorales infections can be polymicrobial: approximately 40% of clinical isolates host bacteria that can be either transiently associated or form obligate holobionts. Our unbiased survey of clinical Mucorales isolates found much more diversity than previously reported. The pairings can encompass a surprising variety of both fungal hosts and bacterial partners, spanning Mucorales genera and both gram positive and negative species. Importantly, our data demonstrate bacteria can mediate fungal virulence by

increasing fungal stress resistance and
secreting factors that block host responses².

Recent clinical reports also suggest Mucorales may be infection reservoirs for bacteremia in vivo^3,4. Disrupting holobionts can reduce fungal fitness². Together, these findings suggest that compounds that disrupt holobionts may offer an important opportunity for controlling and mitigating fungal infections. Finally, our work swapping fungal host and bacterial partner reveal growth of non-host fungi can be controlled by bacterial secreted factors. This suggests such bacteria may represent an untapped source of antifungal compounds.

This project will identify inhibitors of Mucorales-bacterial interactions underpinning virulence, and fill a major gap in knowledge around biologically relevant secreted products. The student will:

Perform HTP screens to disrupt holobionts using panels of well-characterised chemical fragments, FDA approved and in-pipeline drugs.
Perform HTP screens for antimicrobial activity using a library of secreted factors generated from fungal isolates.
Prioritize and characterise hits and their modes of action.

Aim 1) Using whole cell screening assays established at the MRC Centre for Medical Mycology, the student will perform a HTP screen for inhibitors of germination in two different Rhizopus holobionts. These representative clinical isolates are genetically tractable to enable downstream functional analyses. The aim serves as a training period for the student in HTP methodologies using well-characterised and stable libraries of compounds (Maybridge 500, Enamine) and will yield novel compounds that can block Mucorales growth.

Aim 2) Mucorales-bacterial interactions can elicit mutualistic or antagonistic outcomes, in part via uncharacterised secreted factors. These are often only produced under specific conditions, (i.e., in co-culture with other microbes). Using a panel of ~ 300 clinical and environmental holobionts and bacteria, the student will screen for inhibitors of microbial growth against a panel of clinically relevant category 2 and 3 fungi and bacteria. Supernatants with antimicrobial activity will be subjected to size exclusion chromotography and HPLC to identify active fractions, and then analysed by LC/MS for known molecules. Novel compounds will be passed on to collaborators for identification by NMR and structural methods, paired with bioinformatic data on gene expression profiles of the source species.

Aim 3) After elimination of pan-assay interference compounds (false-positives), chemicals with favourable potency, spectra of activity and toxicity profiles will be further characterized to rule out targets conserved in humans or that may threaten ecosystem integrity. Remaining compounds will be further characterized for possible modes of action, and analogous compounds sought from commercial suppliers and/or synthesized to seek structure activity relationships. The student will assess inhibitor impact and likely modes of actions on secondary phenotypes, (fungal growth; stress resistance; holobiont stability) and test for synergistic activity with established antifungals. Where a priori knowledge is absent, the student will mine locally available fungal mutant libraries for hyper- or hypo- susceptibility phenotypes.

3.1) Hits will be assessed for toxicity in collaboration with the Dstl. Here the student will receive training in a range of assays to investigate the toxicity of any new compounds identified in Aim 3. These assays will include assessment of mitochondrial toxicity using Seahorse technology, measurement of lactate dehydrogenase and (dependent on the compounds) assessment of immune correlates. In addition, there is the potential to evaluate these compounds in the wax moth Galleria mellonella.

3.2) Working with partners at the Medicines Discovery Institute at Cardiff University, hits will be further characterised to assess drug-like properties. This will comprise predictions of physicochemical properties (including logP/D, PSA) to predict solubility, permeability and absorption [ChemAxon software suite] and predictions of potential metabolism [Stardop software] as well as measuring kinetic solubility and microsomal turnover (mouse/rat/human). Depending on the number of hits obtained, they will also be ranked and/or clustered to aid onward prioritization.

References

Rodriguez CJ, Ganesan A, Shaikh F, Carson ML, Bradley W, Warkentien TE, Tribble DR. 2022. Combat-Related Invasive Fungal Wound Infections, Military Medicine, 187(2) 34–41,
Itabangi H, Sephton-Clark PCS, Tamayo DT, Zhou X, Starling GP, Mahamoud Z, Insua I, Probert M, Correia J, Moynihan PJ, Gebremariam T, Gu Y, Ibrahim AS, Brown GD, King JS*, Ballou ER*, Voelz K. 2022. A bacterial endosymbiont of the fungus Rhizopus microsporus drives phagocyte evasion and opportunistic virulence. Current Bilogy 32(5):1115-1130.e6.
Tansarli GS, Eschbacher J, Schroeder LK, SenGupta D, Lieberman JA. 2023 Mycetohabitans rhizoxinica in Patients with Rhinocerebral Mucormycosis Due to Rhizopus microsporus. Mycopathologia.
Yang S, Anikst V, Adamson PC. 2022. Endofungal Mycetohabitans rhizoxinica Bacteremia Associated with Rhizopus microsporus Respiratory Tract Infection. Emerg Infect Dis. Oct;28(10):2091-2095.

Eligibility

This studentship is open to applications from candidates who would be classified as UK citizens only.
All studentships are competitively awarded.
Applicants must have obtained, or be about to obtain, a UK degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences.
The DTP also welcomes students from non-medical backgrounds, especially in areas of computing, mathematics, and the physical sciences.
Academic qualifications are considered alongside any significant relevant non-academic experience.
If English is not your first language, you will need to meet the English language requirements of the university that will host your PhD by the start of the programme, Please refer to the Exeter University website here for further information on this.

Funding Notes

Throughout the duration of the studentship, there will be opportunities to apply to the Flexible Funding Supplement for additional support to engage in high-cost training opportunities.

How to apply and additional information

Please submit an application to the GW4 BioMed2 MRC DTP for an offer of funding. The closing date for application is Friday 16^th June 2023 at 5pm.

Available Projects