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
Entry Requirements
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.
Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.
How To Apply
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships
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/
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