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(BBSRC DTP) Discovery and Editing Pathways to New Antibiotics


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 also develop methods to diversify/optimise the structure of these molecules if we are to combat emerging antimicrobial resistance (AMR). In this project, we aim to use state-of-the-art synthetic biology technologies, including CRISPR-cas9 gene editing and directed evolution, to create new enzymes and pathways that deliver novel antibiotics. We will focus on hybrid nonribosomal peptide and polyketide natural products that show promising antimicrobial activity. Initially we will characterise the key enzymes required for the biosynthesis of these 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 this knowledge to guide engineering of NRPS/PKS enzymes that accept alternative substrates and evolve new tailoring enzymes 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 pathways that can deliver new antibiotics which are urgently required to combat AMR.
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.

http://www.manchester.ac.uk/research/Jason.micklefield/
http://www.micklefieldlab.chemistry.manchester.ac.uk
https://twitter.com/Micklefield_Lab
http://www.manchester.ac.uk/research/david.leys/

Entry Requirements:
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.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Partnership. 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 View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

[1] A vitamin K-dependent carboxylase is involved in antibiotic biosynthesis. B. J. C. Law, Y. Zhuo, D. Francis, M. Winn, Y. Zhang, M. Samborskyy, A. Murphy, P. F. Leadlay & J. Micklefield. Nature Catalysis 2018, 1, 977-984 (http://dx.doi.org10.1038/s41929-018-0178-2)
[2] De novo Biosynthesis of 'Non-Natural' Thaxtomin Phytotoxins. M. Winn, D. Francis & J. Micklefield, Angew. Chem. Int. Ed. 2018, 57, 6830-6833. (http://dx.doi.org/10.1002/anie.201801525)
[3] RadH: A Versatile Halogenase for Integration into Synthetic Pathways. B. R. K. Menon, E. Brandenburger, H. H. Sharif, U. Klemstein, M. F. Greaney & J. Micklefield Angew. Chem. Int. Ed. 2017, 56, 11841–11845 (http://dx.doi.org/10.1002/anie.201706342)
[4] 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)
[5] 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)
[6] 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)

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