We have three fully funded PhD studentships available for start in October 2026 - details below. If you have specific questions that are not covered in the ad or on the PhD programme webpages, please contact Rob directly. We are also happy to consider students who source their own funding. If you are eligible for external funding sources and would like to discuss these or another project aligned with our lab interests, get in touch.

Project 1:

Doubling down: determining the dual function of VanT in C. difficile antibiotic resistance.

Dr Rob Fagan, Prof Gavin Thomas and Prof Marjan van der Woude

Antimicrobial resistance is one of the greatest challenges facing humanity. Given the enormous barriers to the development of new antibiotics, it is critical that we prolong the effectiveness of current treatments. To this end, understanding the mechanisms of emerging antimicrobial resistance is incredibly important. We are focussing on the human pathogen Clostridioides difficile, which kills more than 2,000 people every year in the UK alone, with cases increasing 34% since 2020. C. difficile is intrinsically resistant to many antibiotics, and thrives in the disrupted gut environment following antibiotic treatment (1). Vancomycin is the frontline treatment in the UK but there are worrying signs that resistance is emerging. We found that 4% of recent UK isolates were resistant and in one localised outbreak resistance was more than 30%. Our group in Sheffield has shown that the vanG gene cluster is a major driver of vancomycin resistance (2, 3). One of these genes, vanT, encodes a protein with a serine racemase domain that is known to contribute to vancomycin resistance and a second previously uncharacterised membrane domain, which we have recently shown to be an acyltransferase that had been completely ignored until now (4-6). We hypothesise that this domain also contributes to vancomycin resistance, either through direct modification of the antibiotic or through modification of the cell envelope to make the antibiotic less effective.

In this project you will be the first to shed light on the full role of VanT in vancomycin resistance. You will use a combination of bacteriology, molecular biology (mutations, gene expression) and biochemistry (protein purification, biophysical analyses) to determine the function of this important VanT protein. You will identify the cellular target of the acyl transferase using our collection of wild type and evolved mutant enzymes, elucidate the role of this activity in vancomycin resistance and recapitulate the resistance mechanism in the lab. This is an opportunity for you to contribute to one of the greatest medical challenges we face today and have real-world impact in how we treat a hugely important human pathogen.

You will receive training in state-of-the-art bacterial genetics and biochemical methods and will have opportunities to attend and present your work at national and international conferences. You will join a lab with a history of championing diversity and student independence and be embedded within a wider community of PhD students and microbiologists in Sheffield and in research visits to York. You will contribute to our informal group meetings and shared lab meetings where you will interact with scientists from a range of disciplines all working on microbiological problems. As a member of our Florey Institute you will also interact regularly with staff and PhD students from across the University, as well as clinical colleagues from our local NHS Trust.

References

1. Pathogenicity and virulence of Clostridioides difficile. Virulence (2023) 14: 2150452. https://doi.org/10.1080/21505594.2022.2150452

2. A novel two-component system controls vancomycin resistance in epidemic Clostridioides difficile. bioRxiv (2025) https://doi.org/10.1101/2025.08.21.671617

3. Identification of pathways to high-level vancomycin resistance in Clostridioides difficile that incur high fitness costs in key pathogenicity traits. PLoS Biology (2024) 22: e3002741. https://doi.org/10.1371/journal.pbio.3002741

4. Structural unification of diverse transmembrane acyltransferases reveals a conserved fold for the Transmembrane Acyl Transferase (TmAT) superfamily. J. Biol Chem. (2025) 301: 110546. https://doi.org/10.1016/j.jbc.2025.110546

5. A novel fold for acyltransferase-3 (AT3) proteins provides a framework for transmembrane acyl-group transfer. eLife (2023) 12: e81547. https://doi.org/10.7554/eLife.81547

6. Acetylation of surface carbohydrates in bacterial pathogens requires coordinated action of a two-domain membrane-bound acyltransferase. mBio (2020) 11: e01364-20. https://doi.org/10.1128/mbio.01364-20

Project 2:

Life and death in the age of vancomycin: visualising how Clostridioides difficile survives antibiotic treatment at the single cell level.

Dr Rob Fagan and Dr William (Mack) Durham)

Antimicrobial resistance is one of the greatest challenges facing humanity today. Since the barriers to developing new antibiotics are enormous, it is critical that we prolong the effectiveness of our current treatments. Achieving this requires a deep understanding of both how these drugs work and the mechanisms that bacteria evolve to resist them. This PhD project will focus on the human pathogen Clostridioides difficile, which kills more than 2,000 every year in the UK alone (1). C. difficile is intrinsically resistant to many antibiotics, and thrives in the disrupted gut environment created by antibiotic treatment. Vancomycin is the frontline treatment in the UK, but we have recently shown that high level resistance can evolve rapidly in the laboratory (2, 3) and there are worrying signs that resistance is also emerging in clinical settings. Although vancomycin is widely used to treat C. difficile infection we know surprisingly little about how the bacteria respond to this drug.

In this project we will use a combination of molecular microbiology and advanced live cell anaerobic microscopy to study the mechanism of vancomycin-induced cell death at single cell resolution. We will study how evolving resistance prevents cell death and how C. difficile cells respond to the antibiotic concentrations they experience in the human patient. By simultaneously imaging thousands of cells, we will quantify how the morphology and protein expression of surviving cells differs from those that die, allowing us to test how C. difficile evades treatment in humans.

You will receive broad training in state-of-the-art bacterial genetics, advanced live cell microscopy and computational methods for single cell data analysis. You will join a lab with a history of championing diversity and student independence and will be embedded in a vibrant, supportive community of microbiologists in Sheffield.

References

1. Pathogenicity and virulence of Clostridioides difficile. Virulence (2023) 14: 2150452. https://doi.org/10.1080/21505594.2022.2150452

2. A novel two-component system controls vancomycin resistance in epidemic Clostridioides difficile. bioRxiv (2025) https://doi.org/10.1101/2025.08.21.671617

3. Identification of pathways to high-level vancomycin resistance in Clostridioides difficile that incur high fitness costs in key pathogenicity traits. PLoS Biology (2024) 22: e3002741. https://doi.org/10.1371/journal.pbio.3002741

Project 3:

Predicting pathogen evolution: using experimental evolution to understand the impact of phage therapy on Clostridioides difficile 

Dr Ellie Harrison and Dr Rob Fagan

Antimicrobial resistance is one of the greatest challenges facing humanity today. We desperately need new therapeutic options and phage therapy - using viruses that kill bacteria - is widely seen as one such approach. However, in order to avoid repeating the mistakes of the past and ensure phage therapy is used to its full potential, we must develop a deeper understanding of the ecological and evolutionary interactions between phages and their target bacteria. We are focussing on the important human pathogen Clostridioides difficile, which kills more than 2,000 every year in the UK alone. C. difficile is intrinsically resistant to many antibiotics, and thrives in the disrupted gut environment created by antibiotic treatment. For this reason, alternative therapeutics - such as phages - are vital. 

However, C. difficile is a spore forming bacteria - able to form metabolically dormant endospores resistant to harsh environments - and phage infection. Evolutionary theory suggests that sporulation may have dramatic impacts on bacteria-phage dynamics, potentially driving unexpected - and unwanted - consequences for infections. This project will leverage our groups’ expertise in experimental evolution (Harrison) and Clostridial cell biology and genetics (Fagan) to dissect the evolutionary interplay between predator and prey in real time. This work will develop the underpinning understanding necessary to make C. difficile phage therapy viable. Specifically, we will use experimental evolution, combined with genome sequencing and molecular genetics to determine how phage predation affects the efficiency of sporulation and how the ability to sporulate affects phage virulence. 

You will receive broad training in state-of-the-art bacterial genetics, experimental evolution and phage biology. You will join a lab with a history of championing diversity and student independence and be embedded in a wider lab group of microbiologists in the School of Biosciences. 

EMBO provide funding for 2 year fellowships for internationally mobile candidates. See the EMBO webpage for more information and get in touch with Rob if you'd like to discuss a possible application.

Very similar to the EMBO fellowships above, the Marie Skłodowska-Curie fellowships support postdocs moving within Europe (including the UK) for 1-2 years. The 2025 round will be opening soon, with a deadline in September. If you are interested in exploring a potential collaboration with us for your fellowship please get in touch with Rob.