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(A*STAR) Engineering pathways to next generation antibiotics


Project Description

The provision of new antibiotics to combat antimicrobial resistance (AMR) and to treat neglected tropical diseases (NTD), which are problematic in the developing world, is a major global challenge. Most of the of antibiotics in clinical use today are derived from microbial secondary metabolites (natural products) which were discovered more than 40 years ago. The Actinobacteria (e.g. Streptomyces) have been the most prolific source of antibiotics to date, providing many of the essential antibacterial, antifungal and antiparasitic agents. However, many of the old antibiotics are becoming ineffective due to AMR and consequently there is urgent need for new antibiotics with novel structures. In this project, we will exploit recent advances in genomics, synthetic biology and structural biology to engineer and rapidly optimise new antibiotic scaffolds to combat AMR and NTD. We will focus on hybrid nonribosomal peptide and polyketide natural products, from Streptomyces, that show promising antimicrobial activity. We will then use structural and mechanistic knowledge to guide engineering of the 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 novel antibiotics, which are urgently required to combat AMR.

The project will involve a collaboration between the Micklefield lab at the Manchester Institute of Biotechnology (MIB) and Ee Lui Ang’s Metabolic Engineering Research Laboratory (MERL) at the Institute of Chemical and Engineering Sciences (A*STAR) in Singapore. The student will spend two years in Manchester and two years in Singapore. Training in Manchester will cover natural products chemistry, protein engineering, directed evolution, enzyme characterisation and enzyme assays. In Singapore the student will develop further skills in synthetic biology, 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, biosynthesis (natural products), microbiology, synthetic biology or a related science are encouraged to apply.

For more information see:
http://www.manchester.ac.uk/research/Jason.micklefield/
http://www.micklefieldlab.chemistry.manchester.ac.uk
https://www.a-star.edu.sg/merl/Members
https://twitter.com/Micklefield_Lab

Entry Requirements:
Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. 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 available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Singapore, as outlined on 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

Examples of recent related research from Manchester and A*STAR:
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] CRISPR –Cas9 strategy for activation of silent Streptomyces biosynthetic gene clusters. M. M. Zhang, F. Wong, Y. Wang, S. Luo, Y. H. Lim, E. Heng, W. L. Yeo, R. E Cobb, B. Enghiad, E.L. Ang & H. Zhao. Nature Chemical Biology 2017, 13, 607–609. (http://dx.doi.org/10.1038/nchembio.2341)
5] Twin-primer non-enzymatic DNA assembly: an efficient and accurate multi-part DNA assembly method. J. Liang, Z. Liu, X.Z. Low, E.L. Ang & H. Zhao. Nucleic Acids Research 2017, 45, e94 (https://doi.org/10.1093/nar/gkx132)
6] A highly efficient single-step, markerless strategy for multi-copy chromosomal integration of large biochemical pathways. S. Shi, Y. Liang, M.M. Zhang, E.L. Ang & H. Zhao. Metabolic Engineering 2016, 33, 19-27 (https://doi.org/ 10.1016/j.ymben.2015.10.011).

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