About the Project
The global increase of antimicrobial resistance is among the most important healthcare issues currently. An estimated 700,000 deaths annually are due to infections by drug-resistant microorganisms. Historically, the majority of antibiotics come from natural products. However, the rate of new antibiotic discovery has slowed significantly in recent years and we aim to address this issue by tackling two key issues:
1. Can we improve the efficiency of novel natural product discovery from microorganisms?
Although microorganisms contain the genes for producing many natural products, these are usually unexpressed under laboratory conditions. Our approach is to activate these silent genes through small molecules that inhibit epigenetic enzymes. In preliminary experiments, we have successfully employed the technique in fungi, algae and bacteria.
2. Can we improve known natural product antibiotics that are not in clinical use?
Many antibiotics are promising in laboratory assays but insufficiently active or suffer from pharmacokinetic liabilities that prevent their in vivo use. Our approach is to make these antibiotics by total synthesis, which then allows us to generate libraries of synthetic analogues with improved properties. Among natural product antibiotic targets are teixobactin, rufomycin and telomycin.
The PhD project is interdisciplinary and you will receive training in microbial fermentation, natural product isolation, structure elucidation, organic synthesis, chemical biology and medicinal chemistry. The specifics of the project will be individually tailored to fit your background and research interests.
Applicants need to be highly motivated about postgraduate studies and should have an undergraduate degree in Pharmacy, Chemistry, Biology or a related subject.
For more information on the supervisor for this project, please go here: https://www.uea.ac.uk/pharmacy/people/profile/a-ganesan
Type of programme: PhD
Start date of project: October 2018
Mode of study: Full time
Acceptable first degree: Pharmacy, Chemistry, Biological Sciences.
Minimum entry requirements: Candidates must have, or expect to achieve, a First or Upper Second Class Honours Degree or international equivalent.
References
1. Conforti, F.; Davies, E. R.; Calderwood, C. J.; Thatcher, T. H.; Jones, M. G.; Smart, D. E.; Mahajan, S.; Alzetani, A.; Havelock, T.; Maher, T.; Molyneaux, P. L.; Thorley, A. J.; Tetley, T. D.; Warner, J. A.; Packham, G.; Ganesan, A.; Skipp, P. J.; Marshall, B. J.; Richeldi, L.; Sime, P. J.; O'Reilly, K. M. A.; Davies, D. E. The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis. Oncotarget, 2017, 8, 48737-48754.
2. Borrello, M. T.; Schinor, B.; Bartels, K.; Benelkebir, H.; Pereira, S.; Al-Jamal, W. T.; Douglas, L.; Duriez, P. J.; Packham, G.; Haufe, G.; Ganesan, A. Fluorinated Tranylcypromine Analogues as Inhibitors of Lysine-specific Demethylase 1 (LSD1, KDM1A). Bioorg. Med. Chem. Lett. 2017, 27, 2099-2101.
3. Liu, Q.; Lu, W.; Ma, M.; Liao, J.; Ganesan, A.; Hu, Y.; Wen, S.; Huang, P.; Synthesis and Biological Evaluation of Santacruzamate A and Analogs as Potential Anticancer Agents. RSC Adv. 2015, 5, 1109-1112.
4. Masuda, Y.; Tanaka, R.; Kai, K.; Ganesan, A.; Doi, T. Total Synthesis and Biological Evaluation of PF1171A, C, F, and G, Cyclic Hexapeptides with Insecticidal Activity. J. Org. Chem. 2014, 79, 7844-7853.
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