Supervisors

Lead supervisor- Dr Dirk Sanders, University of Exeter, Department of Biosciences

Co-Supervisors:

Professor Tiffany Taylor, University of Bath, Department of Life Sciences

Professor Angus Buckling, University of Exeter, Department of Biosciences

The GW4 BioMed2 MRC DTP is offering up to 21 funded studentships across a range of biomedical disciplines, with a start date of October 2025.

These four-year studentships provide funding for fees and stipend at the rate set by the UK Research Councils, as well as other research training and support costs, and are available to UK and International students.

About the GW4 BioMed2 Doctoral Training Partnership

The partnership brings together the Universities of Bath, Bristol, Cardiff (lead) and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities, with opportunities to participate in interdisciplinary and 'team science'. The DTP already has over 90 studentships over 6 cohorts in its first phase, along with 58 students over 3 cohorts in its second phase.

The 120 projects available for application, are aligned to the following themes;

• Infection, Immunity, Antimicrobial Resistance and Repair

• Neuroscience and Mental Health

• Population Health Sciences

 

Applications open on 10th September 2024 and close at 5.00pm on 4th November 2024.

Studentships will be 4 years full time.  Part time study is also available.

Project Information

Research Theme:

Infection, Immunity, Antimicrobial Resistance & Repair

Summary

Antimicrobial resistance (AMR) is rising to dangerously high levels causing a global health crisis. To develop strategies to combat AMR, we need to know how AMR genes are spreading. Plasmids as ubiquitous mobile genetic elements are key players of AMR spread. Antibiotics make carry AMR plasmids beneficial to their bacterial hosts and therefore drive plasmid prevalence and evolution. This project will investigate the evolution of highly transmissible AMR plasmids that can spread resistance within and between microbiomes. This will be done by targeted experiments and investigations of complex microbiomes using plasmid genomics and network analysis.

Project Description

The widespread use of antibiotics in clinical and agricultural settings has resulted in the rapid evolution and spread of antibiotic resistance causing a major health crisis (1). Bacteria can gain resistance to antibiotics through mutations or by taking up resistance genes (2). Plasmids play a key role in the spread of antimicrobial resistance (AMR) genes (3) because of their ability to transfer between different bacteria (4). The range of different bacterial hosts that plasmids interact with, i.e. plasmid generalism, is therefore crucial for the spread of AMR. There is evidence that antibiotic pressure can enhance plasmid generalism and this may not only facilitate the spread of the AMR genes under selection, but also may allow additional AMR genes to hitchhike along with the generalist plasmids (5). This could then lead to the spread of multi-drug resistant plasmids throughout microbial communities and, more worryingly, between environmental, agricultural and clinical microbiomes, a threat acknowledged in the OneHealth concept (2). AMR plasmid spread could be mitigated if plasmid generalism is a transient effect, reducing when antibiotic selection is lowered. However, it is unclear if this is the case. Plasmids can evolve incredibly quickly (6), and continued exposure to multiple hosts may lead to the evolution of
plasmids that are even more successful at transmitting within microbiomes (7). Exposure to even a single antibiotic may lead to the evolution of plasmids that are highly infectious vectors of AMR genes in general.

This project aims to determine how plasmids become transmissible AMR vectors. It will be experimentally tested how environmentally relevant antibiotic exposure regimes shape plasmid generalism and determine the molecular/functional changes on the plasmid. The project will further investigate the spread of AMR plasmids in complex communities (host-plasmid networks) and to pathogens combined with theoretical modelling.

Key question

Is evolved plasmid generalism the driver of AMR spread to pathogens within microbiomes? With increased plasmid generalism, we can expect significant changes to the structure of host-plasmids networks, becoming more interconnected and plasmids transmitting between phylogenetic distant hosts. This will have consequences for future events of novel AMR genes spread across microbial communities.

Objectives

1. Determine if antibiotic exposure leads to evolved plasmid generalism.

AMR plasmids within replicate complex experimental bacterial communities will be exposed to different levels of antibiotics for 6 weeks. Host-plasmid network structures and plasmid generalism will be measured at the end of the experiment. This objective aims to measure the (under different antibiotic pressures) evolved plasmid fitness effects across a range of hosts and to determine the genomic basis of evolved plasmid generalism. RNA sequencing on ancestral and evolved bacteria with and without the plasmid will reveal gene expression networks for generalist plasmids compared to specialist plasmids.
2. Test experimentally if plasmid generalism can predict the spread of AMR plasmids to pathogens in complex host plasmid networks. Link plasmid generalism to network structure and risk of pathogens gaining resistance. We will expose laboratory scale wastewater communities spiked with known AMR plasmids to relevant antibiotic
exposure regimes and determine the resultant bacteria-plasmid networks using Hi-C metagenomics. This will allow to determine how antibiotics shape bacteria-plasmid network structure and the spread of AMR in wastewater microbiomes and to pathogens. The student will have the choice of studying a type of microbiome, e.g. soil, sewage or porcine gut (faecal) microbiome.
3. Determine the drivers of plasmid invasion of new microbiomes. We will complement the experimental work with theory to identify possible interventions to minimise AMR spread. An example for such intervention is to reduce antibiotic concentration/diversity in the environment to minimise transmission between microbiomes. As a
starting point, we will use published models developed for communities containing multiple hosts and plasmids with and without antibiotics (8,9). The models describe ecological dynamics of bacteria-plasmid communities based on Lotka-Volterra competition, including horizontal transmission and plasmid loss. We will vary costs associated with plasmid generalism and the strength and specificity of selection (i.e., multiple antibiotics and resistance mechanisms). The experiments and the wider work of the supervisor team will provide crucial data about plasmid and host traits related to their importance within the networks and for AMR transmission. We will explore how plasmid survival and spread in a new environment is affected by the amount of invading host
bacteria, growth rate costs of bacteria in new environments, the degree of evolved generalism, and antibiotic selection within hosts. Here the student has the freedom exploring different approaches and interventions.
References
1. Murray et al. Lancet, 629–655 (2022). 2. Castañeda-Barba et al. Nat.Rev.Microbiol., 1–15 (2023). 3. DelaFuente et al. Nat.Ecol.Evol., 1980–1991 (2022). 4. Redondo-Salvo et al. Nat.Commun., 3602 (2020). 5. Lassalle et al. Nat.Microbiol., 1787–1798 (2023). 6. Dimitriu et al. PNAS, e2107818118 (2021). 7. De Gelder et al. Genetics, 2179–2190 (2008). 8. Newbury et al. PNAS, e2118361119 (2022). 9. Risely et al. Nat.Commun. 15, 555 (2024).

Funding

This studentship is funded through GW4BioMed2 MRC Doctoral Training Partnership. It consists of UK tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£19,237 p.a. for 2024/25, updated each year).

Additional research training and support funding of up to £5,000 per annum is also available.

Eligibility

Residency:

The GW4 BioMed2 MRC DTP studentships are available to UK and International applicants. Following Brexit, the UKRI now classifies EU students as international unless they have rights under the EU Settlement Scheme. The GW4 partners have agreed to cover the difference in costs between home and international tuition fees. This means that international candidates will not be expected to cover this cost and will be fully funded but need to be aware that they will be required to cover the cost of their student visa, healthcare surcharge and other costs of moving to the UK to do a PhD.  All studentships will be competitively awarded and there is a limit to the number of International students that we can accept into our programme (up to 30% cap across our partners per annum).

Academic criteria:

Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences.  Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English requirements:

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 details in the following web page for further information https://www.exeter.ac.uk/study/englishlanguagerequirements/

Data Protection

If you are applying for a place on a collaborative programme of doctoral training provided by Cardiff University and other universities, research organisations and/or partners please be aware that your personal data will be used and disclosed for the purposes set out below.

Your personal data will always be processed in accordance with the General Data Protection Regulations of 2018. Cardiff University (“University”) will remain a data controller for the personal data it holds, and other universities, research organisations and/or partners (“HEIs”) may also become data controllers for the relevant personal data they receive as a result of their participation in the collaborative programme of doctoral training (“Programme”).

Further Information

For an overview of the MRC GW4 BioMed programme please see the website www.gw4biomed.ac.uk

Entry requirements

Academic Requirements

Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences. Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English Language Requirements

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 relevant university website for further information.  This will be at least 6.5 in IELTS or an acceptable equivalent.  Please refer to the English Language requirements web page for further information.

How to apply

A list of all the projects and how to apply is available on the DTP’s website at gw4biomed.ac.uk.  You may apply for up to 2 projects and submit one application per candidate only.

Please complete an application to the GW4 BioMed2 MRC DTP for an ‘offer of funding’.  If successful, you will also need to make an application for an 'offer to study' to your chosen institution.

Please complete the online application form linked from our website by 5.00pm on Monday, 4th November 2024.  If you are shortlisted for interview, you will be notified from Friday, 20th December 2024.  Interviews will be held virtually on 23rd and 24th January 2025.

Further Information

For informal enquiries, please contact GW4BioMed@cardiff.ac.uk

For project related queries, please contact the respective supervisors listed on the project descriptions on our website.

Summary