This PhD opportunity is being offered as part of the LSTM and Lancaster University Doctoral Training Partnership. Find out more about the studentships and how to apply.
| Abstract | Uropathogenic Escherichia coli (UPEC) are the primary cause of urinary tract infections (UTIs), which are a significant global health burden and source of morbidity in women and a leading cause of antibiotic prescriptions. The increasing prevalence of antimicrobial resistance (AMR) among UPEC strains complicates treatment and underscores the need for a deeper understanding of their pathogenic and AMR mechanisms. This project aims to elucidate the genomic determinants of virulence and AMR in UPEC and to investigate how these factors contribute to infection. A collection of clinical UPEC isolates will be whole genome sequenced to comprehensively identify AMR genes, virulence factors, and genomic features associated with pathogenicity. Phenotypic analyses, including biofilm formation assays, will be conducted to correlate genetic profiles with functional traits. Furthermore, a high-throughput bladder organoid platform will be employed to model host-pathogen interactions and assess virulence in a physiologically relevant system. By integrating genomic, phenotypic, and organoid-based data, this project aims to provide novel insights into UPEC pathogenesis and AMR, potentially informing the development of targeted therapeutic strategies for virulence and to overcome AMR. |
| Where does this project lie in the translational pathway? | T1 - Basic Research |
| Methodological Aspects | Methods are interdisciplinary, with microbiology (culturing and conducting phenotypic assays with UPEC isolates), tissue culture (propagating bladder cell lines), organoid development (using LLSA E3 organoid platform so robotics, basic AI programming for wet lab work), whole genome sequencing and bioinformatics. |
| Expected Outputs | At least two high impact publications will be anticipated. These isolates were collected as part of an Innovate UK grant led by Daire Cantillon and so these isolates have already been collected, banked and semi-investigated using basic microbiology assays. This project will build on these preliminary data with a publication on genomic analyses of UPEC isolates and identification of virulence and AMR determinants, biofilm phenotypes and correlations with genomic findings. A second paper will be expected on mechanistic insights from bladder organoid infection models as there is a lack of advanced infection models using UPEC clinical isolates. This project will be essential in generating data for follow on funding building on the successful completion of an Innovate UK grant. MRC will be particularly targeted for funding applications as there is a significant gap in UTI research with translational outputs. I will focus on developing therapeutic interventions and models for virulence of UTIs. The project will enhance understanding of UPEC pathogenesis and AMR, directly informing strategies to combat UTIs and multidrug-resistant infections. Methodologically, it will demonstrate the utility of high-throughput organoid platforms for infection research, contributing to broader translational approaches in microbiology. Additionally, the student will acquire interdisciplinary skills in genomics, bioinformatics, microbiology, and organoid biology, equipping them for their onward careers. |
| Training Opportunities | Building on previous MRC DTP students’ experience, there will be a residential bioinformatics training course for one week offered, provided by the University of Birmingham. Full lab training will be provided covering wet lab and organoid work, supported by both Fabrice and Giancarlo in addition to Daire. |
| Skills Required | Student must possess experience of working in a lab in either microbiology or tissue culture. A life sciences degree such as biochemistry, microbiology or genetics would be preferred as would a relevant masters but I would also be keen to consider students who have industry or research experience in lieu of a Masters. |
| Subject Areas | Antimicrobial Resistance |
| Key Publications associated with this project |
D. Cantillon: A high-resolution genomic and phenotypic analysis of resistance evolution of an Escherichia coli strain from a critically unwell patient treated with piperacillin/tazobactam: https://pubmed.ncbi.nlm.nih.gov/40388325/ D. Cantillon: Three-dimensional low shear culture of Mycobacterium bovis BCG induces biofilm formation and antimicrobial drug tolerance: https://pubmed.ncbi.nlm.nih.gov/33526771/ D. Cantillon: Spontaneously Occurring Small-Colony Variants of Staphylococcus aureus Show Enhanced Clearance by THP-1 Macrophages: https://pubmed.ncbi.nlm.nih.gov/32595630/ F. Graf: β-lactamase expression induces collateral sensitivity in Escherichia coli https://pubmed.ncbi.nlm.nih.gov/38830889/ G. Biagini: An accessible 3D HepG2/C3A liver spheroid model supporting the complete intrahepatocytic lifecycle of Plasmodium falciparum: https://pubmed.ncbi.nlm.nih.gov/40539550/ |