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(BBSRC DTP) Sugaring the pill: a new tactic for combatting antimicrobial resistance


   Department of Chemistry

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  Dr Simon Webb, Prof S Flitsch, Prof E Takano  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

The emergence of antimicrobial resistance (AMR) in pathogens, such as Staphylococcus aureus, is a grave threat for elderly and/or immunocompromised patients. The development of novel therapeutic technologies to treat drug-resistant infections is essential to prevent the spread of these virulent microbes, especially in hospital settings. This project seeks to expand the number of antibiotics that can be used to treat AMR infections by reducing the off-target toxicity of membrane-active peptide antibiotics. Since the loading antibiotics into liposomes (self-assembled drug delivery particles) is an established method for reducing in vivo toxicity,[1] we hope that adding a cell-targeting coating on the liposome surface should ensure more efficient delivery of these antibiotics to pathogens. 

This project will focus on the peptaibol class of membrane-active antibiotics, which will be embedded in the membranes of liposomes that are coated with cell-targeting oligosaccharides. Two research pathways will be used to create a novel peptaibol delivery system that will combat AMR pathogens. Building on our recently published results, chemical synthesis and analysis will be used to create synthetic mimics of peptaibols that have lower off-target toxicity whilst maintaining high activity against selected microorganisms.[2,3] Then a chemoenzymatic approach will be used to create bacteria-targeting oligosaccharides that will be attached to the surface of liposomes.[4] Once the oligosaccharide-coated liposomes have been developed, the efficacy against bacteria of different synthetic peptaibol formulations will be determined, starting with the peptides on their own, then when the peptides are embedded in unmodified liposomes and finally embedded in bacteria-targeting liposomes. The best candidates will then be further analysed through the University of Manchester’s antimicrobial resistance network.[5] 

The successful PhD candidate will join a multidisciplinary team from the MIB (Profs. Flitsch and Takano) and the Chemistry Building (Prof. Webb). The supervisory team will train the applicant in diverse areas, which will include: chemical synthesis and ion channel characterisation; synthetic biology/industrial biotechnology, using glycosyltransferases for preparative biotransformations; synthetic biology/antimicrobial discovery, bacterial cell culture, analysis of antibiotic activity. 

 www.webblab.org  

https://flitschlab.com/  

https://www.research.manchester.ac.uk/portal/eriko.takano.html  

Eligibility

Applicants must 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, engineering or technology. 

Before you Apply

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How To Apply

To be considered for this project you MUST submit a formal online application form - full details on eligibility how to apply can be found on the BBSRC DTP website https://www.bmh.manchester.ac.uk/study/research/bbsrc-dtp/

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [Email Address Removed]

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/


Funding Notes

Studentship funding is for 4 years. This scheme is open to both the UK and international applicants. We are only able to offer a limited number of studentships to applicants outside the UK. Therefore, full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

[1] Allen, T. M.; Cullis, P. R. Adv. Drug Deliv. Rev. 2013, 65, 36–48.
[2] Peters, A. D.; Borsley, S.; della Sala, F.; Cairns-Gibson, D. F.; Leonidou, M.; Clayden, J.; Whitehead, G. F. S.; Vitórica-Yrezábal, I. J.; Takano, E.; Burthem, J.; Cockroft S. L.; Webb, S. J. Chem. Sci. 2020, 11, 7023-7030.
[3] Adam, C.; Peters, A. D.; Lizio, M. G.; Whitehead, G. F. S.; Diemer, V.; Cooper, J. A.; Cockroft, S. L.; Clayden, J.; Webb, S. J., Chem. Eur. J. 2018, 24, 2249–2256.
[4] Silva, J.; Spiess, R.; Marchesi, A.; Flitsch, S. L.; Gough, J. E.; Webb, S. J. J. Mater. Chem. B, 2022, 10, 5016-5027.
[5] https://sites.manchester.ac.uk/antimicrobial-strategy-manchester/

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