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Genome mining of novel bacterial carbazole natural products from new bacterial strains


Department of Chemistry

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Dr H Deng , Dr L Trembleau Applications accepted all year round Self-Funded PhD Students Only

About the Project

The discovery of natural products, an important source of human medicines, is critical for the development of new therapeutics against health threats, including cancer and multidrug-resistant pathogens. Yet, in recent years, industrial efforts for natural product discovery has been hampered due to a variety of reasons, including the repeated discovery of previously known compounds. 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 bacterial carbazole alkaloids (CAs) using available genomic data. Carbazole constitute an important nucleus in many pharmaceutically important agents. Naturally occurring CAs are mainly discovered from plants and fungi. Only a few PAs have been discovered from bacteria to date. Bacterial CAs display promising antibacterial and antitumour activities and have attracted considerable interest from academic research groups and the pharmaceutical industry.

In our previous studies, we identified neocarazostatin A, from the soil bacterium Streptomyces sp. MA37. Bioinformatics analysis, whole pathway expression and gene deletion confirmed that legonmycins originate from tryptophan, acetate and pyruvate as substrates. We further discovered the three new enzymes involved in the carbazole pathway.

Blast search allowed identification of a group (approx. 11) of gene clusters which share high sequence identity (60-80%) to the genes in the neocarazostatin biosynthesis. It is likely that these strains have the potential to produce CA-like metabolites. Furthermore, analysis of the genes in the close proximity of these orfs suggested that these identified gene clusters encode completely different sets of tailoring enzymes that were predicted to modify the CA ring system. Therefore, these bacteria may have potential to produce new CA-like metabolites with structural diversity.

Research objectives: 1. Metabolic profiling of the extracts from these cultures to identify the potential producer of new CAs. 2. Identification and isolation of these unknown CA-like 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 CA-like metabolites.

The successful candidate should have (or expect to have) a UK Honours Degree (or equivalent) at 2.1 or above in Organic chemistry, microbiology or biochemistry or bioorganic chemistry.

Knowledge: 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:
This project is advertised in relation to the research areas of the discipline of Chemistry. Formal applications can be completed online: http://www.abdn.ac.uk/postgraduate/apply. You should apply for PhD in Chemistry, to ensure that your application is passed to the correct College for processing. NOTE CLEARLY THE NAME OF THE SUPERVISOR and EXACT PROJECT TITLE ON THE APPLICATION FORM.

Informal inquiries can be made to Dr Deng ([Email Address Removed]) with a copy of your curriculum vitae and cover letter. All general enquiries should be directed to the Graduate School Admissions Unit ([Email Address Removed]).

Funding Notes

There is no funding attached to this project, it is for self-funded students only

References

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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