Dr Stineke van Houte Department of Biosciences, College of Life and Environmental Sciences, University of Exeter
Professor Will Gaze, College of Medicine and Health, University of Exeter
Dr Ben Ashby, University of Bath
Dr Edze Westra, Department of Biosciences, College of Life and Environmental Sciences, University of Exeter
Antibiotic resistance is one of the most pressing problems of our time, with new resistance mechanisms regularly emerging in clinical pathogens, threatening to make even our last resort antibiotics ineffective. This is true for increasing numbers of (opportunistic) pathogens, including bacteria such as Escherichia coli, Klebsiella pneumoniae, and Enterococcus faecium, which - amongst others - frequently cause severe gut, bladder and systemic infections in hospital settings. Discovering ways to reverse the acquisition of antibiotic resistance would be truly ground breaking. One exciting opportunity that recently emerged is CRISPR-Cas9, a genome-editing tool. Several studies showed that CRISPR-Cas9 can remove antibiotic resistance under lab conditions, but it is unclear whether this also works in a real gut where selection for resistance can be strong and where bacteria are embedded in a gut community. This project integrates synthetic biology, in vitro and in vivo experiments and mathematical modelling to predict and test the effectiveness and consequences of CRISPR-Cas9-mediated removal of antibiotic resistance from clinical pathogens in a realistic gut environment. The Van Houte lab has (1) a large collection of clinical isolates of carbapenem-resistant E. coli and K. pneumoniae, and vancomycin-resistant E. faecium, which will be subjected to CRISPR-Cas9 to remove drug resistance, and (2) a collection of conjugative elements and bacteriophages that will be tested as delivery vehicle for CRISPR-Cas9. We will assess how factors such as antibiotics levels, microbial community composition, delivery vehicle host range and transmission mode will influence the efficiency of CRISPR-Cas9 to remove resistance from clinical isolates. Modelling and experiments allows us to assess the knock-on effects of this technology for the wider microbial community composition and function. While previous proof-of-concept work has been limited to test tubes, this project will translate these findings to real gut communities – a key step towards real-life applications of this novel technology. Specifically, we will first carry out in vitro experiments using an artificial gut microbial community established in the Gaze lab. Next, we will perform in vivo tests in an insect model system, established in the Westra lab. Finally, a selection of the most promising variants of this technology will be further validated using a mouse gut colonization model in collaboration with Dr. Fernanda Paganelli (Utrecht University, the Netherlands). The student will be actively involved in these animal experiments, and will follow appropriate training courses. The integration of antibiotic resistance, CRISPR-Cas and microbiome research is highly novel and is supported by established research programmes in the Van Houte, Gaze and Westra laboratories in the ESI at the University of Exeter. Dr. Ben Ashby at Bath University will provide expertise and training in mathematical modelling. This work will contribute to the development of a new and highly promising technology to eradicate antibiotic resistance from the environment. The approach is highly interdisciplinary and the student will be exposed to a wide range of methods and expertise.
To apply for this project, please complete the application form at https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-doctoral-training-partnership-student-appl
by 5pm Friday 25 November 2019.
This studentship is funded through GW4 BioMed MRC Doctoral Training Partnership. It consists of full UK/EU tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£15,009 for 2019/20, updated each year) for 3.5 years.
For further information relating to the funding please see: View Website