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Genome mining of novel antimicrobial natural products from new bacterial strains


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 severe challenges of a clear and urgent need for new classes of antimicrobials.

The discovery of natural products, an important source of human medicines, is critical for the development of new therapeutics against multidrug-resistant pathogens. Many have suggested that the solution lies in genomics and focusing research efforts on strains that encode genes for the biosynthesis of uncharacterized natural products can dereplicate, streamline, and accelerate the discovery process.
This project is designed to maximise the chance of harnessing a group of previously underexploited antimicrobial natural products using available genomic data and new cultivation technology. We have recently isolated several novel actinomycete strains from geologically unique regions in the world. The genomes of these strains have been sequenced and the bioinformatics analysis indicated that these strains have a huge reservoir for new antimicrobial natural product discovery. We discovered several new bioactive compounds and their related biosynthetic pathways in these bacteria through data mining, genetic manipulation, protein overexpression and enzymology studies.

Research objectives: 1. Metabolic profile of the extracts from these cultures to identify the potential producer of antimicrobials using new cultivation technology and genome mining analysis. 2. Identification and isolation of these unknown antimicrobial compounds for structural elucidation; 3. Development of genetic method to confirm the identity of the identified gene cluster in these bacterial strains. 4. Characterization of novel tailoring enzymes involved in the biosynthesis of these drug-like metabolites.

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.

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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