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Chemo-enzymatic Synthesis and Potential Applications of Novel Heterocyclic Alkaloids


Project Description

Antimicrobial resistance (AMR) is rising to dangerously high levels in all parts of the world. In Europe alone, drug-resistant bacteria are estimated to cause 25,000 deaths annually and cost more than US$1.5 billion every year in healthcare expenses and productivity losses. This is against the backdrop that the pharmaceutical and biotechnology industries are investing less and less in antibiotic discovery due to the challenges and complexities in the process, the difficulty and unpredictability of gaining regulatory approval and low profit margins. As a result, only two new classes of antibiotics have been developed in the last 20 years. The accompanying loss of the expertise in the sector only elevates the threat in the battle with AMR. Therefore we face similar challenges of a clear and urgent need for new classes of antimicrobials.

Many of antimicrobials are structurally complex organic molecules, which are often chemically synthesized from fossil derived feedstock, the process of which requires energy intensive processing and is considered by many as non-sustainable for the future. Currently, it is the strategic plan for most of the governments in the world that encourages their own countries to become a bio-based economy and to establish a modern system that is clean, low-carbon and efficient in the future. Industrial biotechnology (IB) uses biological resources for producing and processing materials and chemicals as a way of helping to reduce dependency on fossil fuels. This includes the application of newly discovered enzymes to new applications in the bioscience industries. These novel enzymes could provide a new and "clean" means of chemical synthesis in the pharmaceutical and chemical industry. IB as a means of green and sustainable chemistry is the growing research and many governments are investing significant resources and funding in bio-based chemicals and renewable energy, given environmental issues plus foods and energy.

This project is designed to maximise the chance of harnessing a group of previously underexploited antimicrobial natural products and their biosynthetic enzymes to generate antimicrobial compound libraries for structure-activity relationship studies.

Research objectives: 1. Chemical synthesis of a range of thioesters or small peptidyl molecules. 2. Explore the catalytic capacities of novel enzymes using the synthetic molecules; 3. Identification of new biocatalysts with the aim of finding enzymes with enhanced kinetics and substrate flexibility; 4. Development of novel compound libraries for bioactivity screening.

Candidates should have (or expect to achieve) a UK honours degree at 2.1 or above (or equivalent) in Organic chemistry, microbiology or biochemistry or bioorganic chemistry.

It is essential that the successful applicant has a background in Organic chemistry, microbiology or biochemistry or bioorganic chemistry.

This is a cross-disciplinary project involving elements of organic chemistry, molecular biology and protein chemistry. In this project, you will gain experience in chemical synthesis of small molecules, cloning genes for heterologous expression, as well as using the purified enzymes to carry out biotransformation reactions. You will learn chemical characterization by LC-MS and NMR analyses. You will gain experience in organic chemistry, microbiology, molecular biology as well as protein chemistry.

APPLICATION PROCEDURE:

• Apply for Degree of Doctor of Philosophy in Chemistry
• State name of the lead supervisor as the Name of Proposed Supervisor
• State ‘Self-funded’ as Intended Source of Funding
• State the exact project title on the application form

When applying please ensure all required documents are attached:

• All degree certificates and transcripts (Undergraduate AND Postgraduate MSc-officially translated into English where necessary)
• Detailed CV
• Details of 2 academic referees

Informal inquiries can be made to Dr H Deng (@abdn.ac.uk) with a copy of your curriculum vitae and cover letter. All general enquiries should be directed to the Postgraduate Research School ()





Funding Notes

This project is advertised in relation to the research areas of the discipline of Chemistry. The successful applicant will be expected to provide the funding for Tuition fees, living expenses and maintenance. Details of the cost of study can be found by visiting View Website. THERE IS NO FUNDING ATTACHED TO THESE PROJECTS. Applicants should also be aware that Additional Research Costs of £6,000 per annum are required (above Tuition Fees and Living Expenses) for consumables.

References

Roberson et al, Nat. Prod. Rep. 2014, 31, 1721.
Huang et al. Angew Chemie Int. Ed., 2015, 54, 12697.
Schimming et al., Angew Chemie Int. Ed., 2015, 54, 12702.
Fu et al. Org Lett., 2015, 17, 3046
Fu et al., J. Nat. Prod. 2015, DOI: 10.1021/acs.jnatprod.5b00604.
Huang et al., Org Lett., 2015, DOI: 10.1021/acs.orglett.5b02707.
Schmidt, et al. Chem. Rev. 2012, 112, 3193.
Pieper, et al. Cell, 2010, 142, 39.
Zhang et al. Bioorg. Med. Chem. Lett. 2010, 20, 1881.
Su et al. Org. Biomol. Chem. 2016, 14, 8678.
Su et al. Org. Biomol. CHem. 2017, 15, 3843
Huang et al. Chem. Biol. 2015, 22, 1633.

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