PhD Research Project: Enhancing the activity of existing antibiotics on persistent Streptococcal in

The Florey Institute (http://www.floreyinstitute.com) and Imagine: Imaging Life (http://www.imagine-imaginglife.com) are long term strategic initiatives at the University of Sheffield (2022 Futures) that provide a platform for ambitious research growth in areas that the University of Sheffield is recognised for internationally. The Florey Institute aims to create a world-leading focus on antimicrobial resistance and host-pathogen interactions, from fundamental science to translation. Imagine: Imaging Life aims to combine and harness cutting-edge imaging technologies in super-resolution microscopy, electron microscopy and atomic force microscopy to address key biological questions. This scholarship, as part of the Global Strategic Alliance programme, will position the student in a thriving research environment that will provide international opportunities for training and career development. The scholarship will be held in the laboratories of Dr Rosie Staniforth and Dr Claire Turner in the Department of Molecular Biology and Biotechnology.

Project title: Enhancing the activity of existing antibiotics on persistent Streptococcal infections by targeting amyloid components of biofilm

Group A Streptococcus (GAS) is a human pathogen that primarily infects the skin and oropharynx where it can lead to severe or lethal infections (necrotising fasciitis). Despite their sensitivity to penicillin, treatment failure and recurrent infections are common and aggressive surgical debridement is often the only treatment for deep tissue infections. Biofilm-like formation by GAS, either on mucosal surfaces such as the tonsil or during deep tissue infections may shield against antimicrobials, reducing drug penetrance.

The aim of this project is to characterise a GAS surface adhesion factor, Asp as an amyloid former, using recombinant expression to produce an in vitro model for structural/mechanistic studies using high-resolution electron microscopy. Validation in situ will be done by targeted mutagenesis of Asp in GAS, and heterologous expression of Asp in Lactococcus lactis. The contribution of amyloids to biofilm/adherence of GAS to surfaces and cell lines, including pharyngeal cells, will be measured. We will assess the efficacy of multidrug treatment of GAS by combining antimicrobials with amyloid modifiers.

This project is a new approach to understanding the mechanisms by which this important pathogen causes disease and, crucially how it can resist treatment during infection. We will identify new intervention strategies to stop the spread of GAS and the severity of infection. The combination of biophysical/mechanistic studies with high resolution electron microscopy studies on the recombinant protein together with direct observation in cell culture will result in a substantial advance in our understanding of these processes and provide a unique inter-disciplinary training opportunity.

Please contact Dr Staniforth (r.a.staniforth@sheffield.ac.uk) or Dr Turner (c.e.turner@sheffield.ac.uk) for more information.

Award Details

• Full tuition fees (UK, EU or Overseas).
• An annual, tax-free maintenance stipend at the standard RCUK rate.
These scholarships fund up to 3.5 years full-time study, subject to satisfactory progress.

Eligibility

• You should have, or expect to achieve, a first or upper second class UK honours degree or equivalent. This should be in a relevant area (e.g. Biology, Molecular Biosciences, Biophysics, Biochemistry).
• Anticipated start date October 2017
• Awards are open to UK, EU and international applicants.

How to apply

Scholarships are awarded on a competitive basis - applications are assessed on the basis of academic success and qualifications, experience, research background and a clear and well-articulated reason for being considered. For information on applying, please see https://www.sheffield.ac.uk/postgraduate/research/apply/applying

For more information about the Florey Institute and Imagine, see http://www.floreyinstitute.com and http://www.imagine-imaginglife.com.