EPSRC DTP PhD Project: Organic synthesis meets chemical biology: design of spirocyclic peptides to tackle antibiotic resistance


   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

The University of Bath is inviting applications for the following PhD project commencing on 30 September 2024 under the supervision of Dr Scott Lovell in the Department of Life Sciences with co-supervision from Dr Alex Cresswell (Chemistry) and Dr Maisem Laabei (Life Sciences).

Eligible applicants will be considered for a fully-funded studentship – for more information, see the Funding Notes section below.

Overview of the Research:

Introduction: 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 cell wall biosynthesis. LtaS is an attractive antimicrobial target as Gram-positive bacteria that lack LTA exhibit impaired cell division and growth defects. Despite this, the pharmacology around LtaS remains largely unexplored and inhibitors reported to date lack in vivo stability and/or selectivity.

Aim: The aim of this PhD project is to screen billion-member libraries of ‘SpiroTides’ against LtaS to identify a highly potent, selective, and in vivo active drug candidate. SpiroTides are a newly proposed macrocyclic drug modality that merge a spirocyclic linker and a peptide, with both components synergistically influencing macrocycle topology, binding affinity, and pharmacological properties.

Methodology: Library Generation and Screening: A library of ~20 spirocyclic linkers will be synthesised using innovative photochemistry developed in the Cresswell lab. These linkers will be used to cyclise cysteine-containing peptides displayed on the surface of phage particles to generate billion-member libraries of SpiroTides. A multi-round phage panning approach will then be used to screen SpiroTide libraries against LtaS. Deconvolution of ‘hits’ by bioinformatic analysis of NGS data will enable rapid identification of the optimal SpiroTide.

Hit-to-lead Optimisation: Hit SpiroTides will be applied to a panel of MRSA isolates to assess changes in LTA biosynthesis and growth rate. Counter screens against E. Coli and human HepG2 cells will validate molecule specificity. Finally, in vivo engagement of LtaS will be demonstrated by applying the SpiroTide to Manduca Sexta larvae challenged with S. aureus. After 3 days larvae will be sacrificed, and bacterial titres will be assessed to determine the molecule’s effect on infection progression.

Outcome: This research will validate LtaS as a therapeutic target for treatment of MRSA infections and will provide an optimized SpiroTide for further pre-clinical assessment.

Development Opportunities: The appointed PhD student will develop a wide range of skills in organic synthesis, peptide phage display, microbiology, and bioinformatics.

Project keywords: Organic synthesis, peptide chemistry, antibiotic resistance, directed evolution, automated synthesis

Candidate Requirements:

Applicants should hold, or expect to receive, a First Class or strong Upper Second-Class Honours degree (or equivalent) in Chemistry and a strong motivation to carry out technically challenging research in synthetic organic chemistry, chemical biology, and drug discovery. Previous experience of synthetic organic chemistry beyond core undergraduate teaching (e.g. industrial placement) would be beneficial but not essential.

Non-UK applicants must meet our English language entry requirement.

Enquiries and Applications:

Applicants are encouraged to contact Dr Scott Lovell on email address [Email Address Removed] before applying to find out more about the project and to discuss their suitability for the role.

Formal applications should be made via the University of Bath’s online application form for a PhD in Biology.

In the ‘Funding your studies’ section of the application form, please select ‘EPSRC DTP’ from the first drop-down menu. In the ‘Your PhD project’ section, please quote the project title and lead supervisor’s name in the appropriate fields. Failure to complete these steps will cause a delay in processing your application and may cause you to miss the deadline.

More information about applying for a PhD at Bath may be found on our website.

Equality, Diversity and Inclusion:

We value a diverse research environment and aim to be an inclusive university, where difference is celebrated and respected. We welcome and encourage applications from under-represented groups.

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.

References:

From Dr Scott Lovell (Life Sciences):

[1] “Identification of highly selective covalent inhibitors by phage display”, Lovell et al.Nat. Biotechnol. 2021, 39, 490

From Dr Alex Cresswell (Chemistry):

[2] “Modular, automated synthesis of spirocyclic tetrahydronaphthyridines from primary alkylamines” Cresswell et al., Commun. Chem. 20236, 215

From Maisem Laabei (Life Sciences):

[3] “Improved antibacterial activity of 1,3,4-oxadiazole-based compounds that restrict Staphylococcus aureus growth independent of LtaS function”, Laabei et al., ACS Infect. Dis. 2023, 9, 2141


Biological Sciences (4) Chemistry (6)

Funding Notes

Candidates applying for this project may be considered for a 3.5-year Engineering and Physical Sciences Research Council (EPSRC DTP) studentship. Funding covers tuition fees, a stipend (£18,622 per annum, 2023/24 rate) and research/training expenses (£1,000 per annum). EPSRC DTP studentships are open to both Home and International students; however, 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.

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