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Dissecting the mechanisms of antibiotic resistance in Clostridium difficile

Department of Molecular Biology and Biotechnology

Dr R Fagan Applications accepted all year round Self-Funded PhD Students Only

About the Project

Antibiotic resistance in pathogenic bacteria is one of the greatest health challenges facing humanity today. Without the development of novel antimicrobial therapies, inhibiting novel targets or restoring the efficacy of existing drugs, we are facing a reversal of the dramatic improvements to both human health and lifespan seen over the last 60 years. Clostridium diffiicle is the leading cause of antibiotic-associated diarrhoea in the UK. C. difficile infection is a direct consequence of our use of antibiotics; the organism is highly resistant to a broad range of antibiotics and requires antibiotic disruption of the normal flora to give it a competitive advantage in the gut.

Despite the importance of C. difficile in the context of human health we know surprisingly little about C. difficile pathogenesis and even less about the molecular mechanisms underpinning its remarkably broad range antibiotic resistance. The bacterial cell wall is the target of several classes of antibiotic, including the β-lactams (e.g. penicillin) and glycopeptide antibiotics (e.g. vancomycin). C. difficile is resistant to most commonly used β-lactam antibiotics, however, the basis of this resistance is completely uncharacterised.

This project aims to dissect the mechanisms of resistance to several antibiotics including broad-spectrum β-lactams. We will use a combination of classical microbiology and genetics to identify the genes responsible for conferring resistance and will then use protein biochemistry approaches to determine the mechanisms of resistance. As a starting point we will employ both random transposon mutagenesis and targeted mutagenesis to identify antibiotic sensitive mutants. For the targeted experiments we will seek to examine the contribution of genes with homology to previously identified resistance mechanisms (e.g. the penicillin-binding proteins and β-lactamases).

Science Graduate School

As a PhD student in one of the science departments at the University of Sheffield, you’ll be part of the Science Graduate School – a community of postgraduate researchers working across biology, chemistry, physics, mathematics and psychology. You’ll get access to training opportunities designed to support your career development by helping you gain professional skills that are essential in all areas of science. You’ll be able to learn how to recognise good research and research behaviour, improve your communication abilities and experience technologies that are used in academia, industry and many related careers. Visit to learn more.

Funding Notes

Entry requirements
First class or upper second 2(i) in a relevant subject. To formally apply for a PhD position, you must complete the University's application form using the following link: View Website

*All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information*.
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