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PhD Studentship - (BBSRC DTP) Bioengineering Sustainable Routes to Anti-infective Agents to Combat Future Pandemics

The University of Manchester

Qualification Type: PhD
Location: Manchester
Funding for: UK Students, EU Students
Funding amount: Not Specified
Hours: Full Time
Placed On: 23rd November 2023
Closes: 19th January 2024

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.

There is an urgent need for new anti-infective agents to combat antimicrobial resistance (AMR) and to protect the global population in the event of future pandemics. Most drugs used to treat infectious diseases today are small molecules produced by microorganisms, called natural products, or derivatives thereof. The existing anti-infective agents have become less effective as pathogens evolve resistance to these molecules. Consequently, we need to discover new anti-infectives and also develop methods to diversify/optimise the structure of these molecules, if we are to combat emerging AMR and provide treatments for future pandemics.

In this project we aim to use genome mining to discover new pathways to polyketide antibiotics which can be used to treat infectious diseases, particularly those that are problematic in the developing world. We will then use state-of-the-art synthetic biology technologies, including CRISPR-Cas9 gene editing and directed evolution, to create new enzymes and pathways to optimised polyketide antimicrobials. Initially we will focus on editing pathways to create polyketide antimicrobials with improved efficacy, solubility, and reduced toxicity. Following compound isolation and characterisation, we will test the compounds for antimicrobial activity and toxicity. Insights from antibiotic testing, will be used to establish a structure-activity relationship (SAR) which can guide further engineering of improved antibiotics.

Training will be provided in molecular biology and microbiology, including manipulation of Streptomyces bacteria. The project will also involve elements of protein engineering, directed evolution, enzyme characterisation (including X-ray crystallography) and enzyme assays. Candidates are not expected to have expertise in all these areas at the outset; above all, scientific curiosity, and a desire to work in a multidisciplinary environment are most important. Candidates with a degree in Chemistry, Biochemistry or Biological Sciences and an interest in biosynthesis (natural products), microbiology, enzyme catalysis (biocatalysis), or a related science are encouraged to apply. The project will be supervised by Professor Jason Micklefield, in collaboration with Professor Anthony Green (enzyme engineering expert) and Professor Mike Bromley (anti-microbial testing and drug development expert).

www.micklefieldlab.chemistry.manchester.ac.uk

www.youtube.com/watch?v=qwvvTEa0ehk

www.greenresearchgroup.co.uk/people

research.manchester.ac.uk/en/persons/mike.bromley

sites.manchester.ac.uk/mfig

Please contact the supervisors before you apply: Prof Jason Micklefield jason.micklefield@manchester.ac.uk, Dr Mike Bromley mike.bromley@manchester.ac.uk and Prof Anthony Green anthony.green@manchester.ac.uk

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