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(BBSRC DTP) Synthetic biology approaches for the discovery and diversification of next generation antibiotics

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  • Full or part time
    Prof J Micklefield
    Prof D Leys
    Dr A Green
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

There is an urgent need for new antibiotics. The majority of antibiotics that are used to treat infectious diseases today are small molecules produced by microorganisms, called natural products, or derivatives thereof. The existing antibiotics have become less effective as pathogens evolve resistance to these molecules. Consequently, we need to discover new antibiotics and develop methods to diversify the structure of these molecules in order to develop more effective treatments to combat emerging drug resistant pathogens. In this project, we aim to combine new synthetic biology technologies, along with state-of-the art advancements in natural products bioengineering and directed evolution of enzymes, to deliver novel antimicrobial compounds.

We will focus on nonribosomal peptide (NRP) and polyketide (PK) natural products that show promising antimicrobial activity. Initially we will characterise the key enzymes required for the biosynthesis of the NRP and PK natural products, including non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) assembly line enzymes, as well as the tailoring enzymes that introduce functionality that is essential for activity. We will then use knowledge of the biosynthetic enzymes to develop bioengineering approaches to generate new derivatives with improved activity and properties. For example, we will engineer NRPS enzymes to accept alternative amino acid substrates and create new assembly lines that can generate novel products. In addition to this, new tailoring enzymes will be evolved to derivatise and further diversify the antibiotic scaffolds. The new suite of enzymes will be introduced into an optimised Streptomyces super-host strain to create new biosynthetic pathways that can deliver the antibiotics which are urgently required to combat emerging antimicrobial resistance. In addition, we will use knowledge of the sequence and function of the biosynthetic enzymes we characterise in order to mine genomes for related biosynthetic enzymes, pathways and natural products, which can also serve as a source of new antibiotics.

Training will be provided in protein engineering, directed evolution, enzyme characterisation (including X-ray crystallography) and enzyme assays. There will also be scope within the project to develop skills in molecular biology and microbiology, including manipulation of Streptomyces bacteria. Candidates are not expected to have expertise in 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 enzyme catalysis (biocatalysis), biosynthesis (natural products), microbiology or a related science are encouraged to apply.

Qualification
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Contact for further Information
For more details contact Professor Jason Micklefield ([email protected])

http://www.manchester.ac.uk/research/Jason.micklefield/
http://www.manchester.ac.uk/research/david.leys/

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships

References

Examples of recent related research:
1. An Enzyme Cascade for Selective Modification of Tyrosine Residues in Structurally Diverse Peptides and
Proteins. A.-W. Struck, M. R. Bennett, S. A. Shepherd, B. J. C. Law, Y. Zhou, L. S. Wong, J. Micklefield J. Am. Chem.Soc. 2016 138, 3038–3045 (http://dx.doi.org/10.1021/jacs.5b10928)

2. Engineered Biosynthesis of Enduracidin Lipogyclopeptide Antibiotics using the Ramoplanin Mannosyltransferase Ram29. M.-C. Wu, M. Q. Styles, B. J. C. Law, A. W. Struck, L. Nunns and J.Micklefield Microbiology 2015, 161, 1338-1347 (http://dx.doi.org/10.1099/mic.0.000095)

3. Site-specific bioalkylation of Rapamycin by the RapM 16-O-methyltransferase. B. J. C. Law, A.-W. Struck, M. R.Bennett, B. Wilkinson, J. Micklefield Chemical Science 2015 6, 2885-2892. (http://dx.doi.org/10.1039/C5SC00164A)

4. Introduction of a non-natural amino Acid into a nonribosomal Peptide antibiotic by modification of adenylation domain specificity. J. Thirlway, R. Lewis, L. Nunns, M. Al Nakeeb, M. Styles, A. W. Struck, C. P. Smith, J. Micklefield Angew. Chem. Int. Ed. Engl., 2012, 51, 7181-7184 (http://dx.doi.org/10.1002/anie.201202043)

5. Bioengineering natural product biosynthetic pathways for therapeutic applications. M.-C. Wu, B. Law, B. Wilkinson, J. Micklefield Curr. Opin. Biotechnol., 2012, 23, 931-940. (http://dx.doi.org/10.1016/j.copbio.2012.03.008)

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