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SWBio DTP PhD project: A Covalent Phage Display Approach for the Discovery of Lipoteichoic Acid Synthase Inhibitors


   Department of Life Sciences

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  Dr Scott Lovell  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

This project is one of a number that are in competition for funding from the South West Biosciences Doctoral Training Partnership (SWBio DTP).

The SWBio DTP is funded by BBSRC and involves a partnership of world-renowned universities, research institutes and industry across the Southwest and Wales. This partnership represents a distinctive group of bioscientists with established international, national, and regional networks and widely recognised research excellence. We aim to provide students with outstanding interdisciplinary research training.

Studentships are available for entry in October 2023.

All SWBio DTP projects will follow a structured 4-year PhD programme, combining traditional project-focussed studies with a taught first year which includes directed rotation projects.

Supervisory Team:

Lead supervisor: Dr Scott Lovell, University of Bath, Department of Life Sciences (email: [Email Address Removed])

Co-supervisors: Prof James Spencer (University of Bristol), Prof Jody Mason (University of Bath), Dr Maisem Laabei (University of Bath) and Prof Jean van den Elsen (University of Bath)

The Project:

Background

Infections with multidrug-resistant bacteria like methicillin-resistant Staphylococcus aureus (MRSA) are major threats to human health. Discovering novel druggable targets for antibiotic development is a pivotal task to guarantee effective treatment in the future. Lipoteichoic acid synthase (LtaS) catalyses the synthesis of lipoteichoic acid (LTA) from phosphatidylglycerol and is a key enzyme for S.aureus cell wall biosynthesis. LtaS is an attractive antimicrobial target as Gram-positive bacteria that lack LTA exhibit impaired cell division and growth defects1.

Methodology

In this PhD project, you will use a phage display approach, developed in the Lovell lab, to identify a potent and selective covalent cyclic peptide (CCP) antagonist for LtaS2. You will screen in-house compound libraries to identify covalent fragments that modify Lys299 in the active site of LtaS. Hit fragments will be resynthesized as linchpin derivatives and grafted onto peptide phage display libraries to generate billions of Lys299-directed CCPs to screen against LtaS. You will carry out multiple rounds of phage panning and amplification and perform bioinformatic analyses to prioritize enriched CCPs for synthesis and testing in surface plasmon resonance binding studies.

Working with the Spencer lab you will obtain co-crystal structures of hit CCPs bound to LtaS revealing critical interacting residues and enabling structure-guided optimization of key molecule parameters such as selectivity and proteolytic stability. You will validate the proteome-wide selectivity of CCPs using chemical proteomics approaches. Working with the Laabei and van den Elsen labs you will apply the lead CCP to a panel of MRSA isolates and assess changes in LTA biosynthesis and growth rate. Finally, you will assess the effects of inhibiting LtaS in vivo by incubating the lead CCP with Manduca Sexta Larvae challenged with S.aureus3.

Your PhD research will validate LtaS as an actionable therapeutic target for the treatment of MRSA infections and will provide an optimized molecule for further pre-clinical assessment.

Development Opportunities

This truly interdisciplinary PhD project will provide you with a wealth of training and expertise in cutting-edge drug discovery and biotechnology, bioinformatics, chemical biology, structural biology, and infection biology. You will develop skills in peptide chemistry and phage display and will learn how to carry out bioinformatic analyses of deep sequencing data, perform X-ray crystallography studies and develop in vivo models of S. aureus infection. You will have the opportunity to communicate your research through publishing articles and presenting at national and international conferences.

Project keywords: Covalent Drug Discovery, Peptide Phage Display, Antibiotic Resistance, Structural Biology, Chemical Proteomics.

Requirements:

Applicants should have obtained, or be about to obtain, a First or Upper Second-Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science or technology. Applicants with a Lower Second-Class degree will be considered if they also have Master’s degree or have significant relevant non-academic experience.

In addition, due to the strong mathematical component of the taught course in the first year and the quantitative emphasis in our projects, a minimum of a grade B in A-level Maths or an equivalent qualification/experience* is required.

* Physics A-level (grade B and above) or units in your degree with a significant mathematical component, e.g. maths, statistics, bioinformatics.

Applicants must ensure they highlight their Maths background within their application and to upload any supporting evidence.

If English is not your first language, you will need to have achieved Academic IELTS 6.5 overall (with no less than 6.5 in any of the four skills). Find details of other acceptable tests and further information on our website.

Enquiries and Applications:

Informal enquiries are welcomed and should be directed to the lead supervisor.

Formal applications should be submitted on the University of Bath’s online application form for a PhD in Biosciences.

When completing the form, please identify your application as being for the SWBio DTP studentship competition in Section 3 Finance (question 2) and quote the project title and lead supervisor’s name in the ‘Your research interests’ section.  You may apply for more than one project within the same application, but you should upload a separate (clearly labelled) personal statement for each one, outlining your interest and suitability for that particular project.

See our website for more information about applying for a PhD at Bath.

Equality, Diversity, and Inclusion:

We want to support diverse and inclusive work environments. We therefore welcome applications from individuals regardless of their race, ethnicity, sexual orientation, religion, age, gender, or disability status.

If you have circumstances that you feel we should be aware of that have affected your educational attainment, then please feel free to tell us about it in your application form. The best way to do this is a short paragraph at the end of your personal statement.


Funding Notes

Candidates may be considered for SWBio DTP studentship tenable for 4 years. Funding covers tuition fees, a stipend (£17,668 p/a in 2022/23) plus an allowance for research/training costs, fieldwork, conference attendance and a 3-month placement. Studentships are open to both Home and International students; however, international applicants should note that funding does NOT cover the cost of a student visa, healthcare surcharge and other costs of moving to the UK. In line with guidance from UK Research and Innovation (UKRI), the number of awards available to international candidates will be limited to 30% of the total.

References

1. Chen, S. et al. Identification of highly selective covalent inhibitors by phage display. Nat. Biotechnol. 39, 490–498 (2021).
2. Richter, S. G. et al. Small molecule inhibitor of lipoteichoic acid synthesis is an antibiotic for Gram-positive bacteria. Proc. Natl. Acad. Sci. U. S. A. 110, 3531–3536 (2013).
3. Fleming, V. et al. Agr interference between clinical Staphylococcus aureus strains in an insect model of virulence. J. Bacteriol. 188, 7686–7688 (2006).

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