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(Dual Award PhD with Tsinghua University) Establishing new microbial hosts for heterologous production of next generation antibiotics


Department of Chemistry

, Prof Andrew Pitt Monday, March 15, 2021 Funded PhD Project (Students Worldwide)
Manchester United Kingdom Biochemistry Biotechnology Genetics Microbiology Molecular Biology Organic Chemistry Pharmaceutical Chemistry Structural Biology Synthetic Chemistry

About the Project

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). In addition to essential antibacterial, antifungal and antiparasitic agents, microbial natural products have been developed as antitumour, antiviral, immunosuppressive agents and as cholesterol lowering agents. In many cases the natural products are produced in very small quantities by microbial species that are difficult to cultivate or genetically manipulate. In addition to this, genome sequencing reveals many bacterial strains possess cryptic biosynthetic gene clusters (BGC) that appear to be silent when cultivated in the laboratory. These strains possess the machinery to produce bioactive natural products, but the biosynthetic genes are not expressed in the native hosts. One way to increase production levels, and also to activate expression of cryptic/unproductive BGC, is to transfer the BGC into heterologous host strains which are more genetically tractable and easier to cultivate. Unfortunately, there are a limited number of well characterised hosts available and some of these are not necessarily ideal for production of certain natural product scaffolds. For example, Escherichia coli and yeast have been widely used, but these strains are not known to produce large numbers of secondary metabolites and production of certain types of natural products can be problematic, particularly those generated by nonribosomal peptide synthetase (NRPS), polyketide synthase (PKS) and hybrid NRPS-PKS assembly lines. In this project we will exploit recent advances in synthetic biology to develop new genetic tools for heterologous expression and manipulation of microbial BGC in new Halomonas host strains to produce antibiotics and other important bioactive natural products. Halomonas are halophiles (tolerate high salinity) and can be easily cultivated under nonsterile conditions. In light of this, Halomonas sp. have emerged as a useful host for production of low molecular weight metabolites and also biopolymers. In this project we aim to develop Halomonas further as heterologous host for production of microbial NRPS, PKS and hybrid NRPS-PKS secondary metabolites, which provide many valuable antibiotics and other important therapeutic agents.

The project will involve a collaboration between the Micklefield lab at the Manchester Institute of Biotechnology (MIB) and George Chen, Director of the Center for Synthetic and Systems Biology (CSSB) at Tsinghua University in Beijing. The student will spend two years in Manchester and two years in Beijing. 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 Halomonas 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.

Entry Requirements

Students must meet the entry requirements of both universities, and will be registered at both institutions in the first year of study.

Applicants should hold (or be about to obtain) a minimum 2:1 bachelor's degree (or overseas equivalent), in a relevant discipline, plus a master's degree or extensive research experience. Applicants can be internal or external to The University of Manchester. For applicants whose first language is not English, we require a minimum IELTS score of 6.5.

For more information see:

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

http://www.micklefieldlab.chemistry.manchester.ac.uk

http://life.tsinghua.edu.cn/lifeen/info/1034/1088.htm

synbiodual


Funding Notes

This is a 4 year PhD studentship. You'll spend two years at The University of Manchester and two years at Tsinghua University. Fees at both institutions are covered, and other fantastic funding opportunities include an annual stipend at the minimum Research Councils rate (15,285 for 2020/21) that will be paid to students while in Manchester, and a commensurate stipend while at Tsinghua.
Entry via Manchester is open to UK/EU and international students, excluding Chinese nationals.

References

Examples of recent related research from Manchester and Tsinghua:
• 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)
• 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)
• 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)
• A tight cold-inducible switch built by coupling thermosensitive transcriptional and proteolytic regulatory parts. Zheng Yang, Meng Fankang Wei Weijia; Sun Zhi; Chen
GQ, Lou Chunbo Nucleic Acids Research 47 (21) e137 (2019) doi: 10.1093/nar/gkz785 (2019)
• Functional Polyhydroxyalkanoates by Engineered Halomonas bluephagenesis. Lin-Ping Yu, Xu Yan, Xu Zhang, Xiang-Bin Chen, Qiong Wu, Xiao-Ran Jiang, Chen GQ.
Biosynthesis of Metabolic Engineering 59 (2020) 119-130 (doi.org/10.1016/j.ymben.2020.02.005)
• Rational Flux-Tuning Halomonas bluephagenesis for Co-production of PHB and Ectoine. Ma Hong, Zhao Yiqing, Huang Wuzhe, Zhang Lizhan, Wu Fuqing, Ye
Jianwen, Chen GQ. Nature Communications (2020) 11:3313

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