About the Project
The majority of antibiotics used to treat microbial infections are either natural products or inspired by them. The introduction of such agents starting with the penicillins in the 1940s has had a profound impact upon human healthcare and reduced the burden of microbial infections. However, in recent years, the emergence of microorganisms that are resistant to these antibiotics has led to a renewed threat of infectious diseases. In the UK alone, it is estimated that antibiotic resistant bacterial resistant strains are responsible for 5,000 deaths a year.
One approach to tackling this problem is to develop new drugs that are unrelated to current antibiotics. Once again, Nature provides us with a bountiful supply of secondary metabolites with intricate and unusual structural motifs. The objective of this project will be to achieve the total synthesis of antibiotic natural products with unusual mechanisms of action or selective activity against resistant strains. The total synthesis will be followed by preparation of a series of analogues and their biological profiling with a view to improving upon the natural product in terms of potency, selectivity or drug-like properties.
Our research group has extensive experience in the synthesis of biologically active natural products isolated from terrestrial and marine organisms. These studies are combined with studies on the biosynthesis, mechanism of action and the discovery of structure-activity relationships through analogue synthesis, often in collaboration with other research groups. Our target molecules range from heterocyclic alkaloids, polyketides, terpenoids to peptides and depsipeptides. The specific antibiotic targets will be selected for you based on your background, experience and research interests. Examples of antibiotics we are currently targeting include teixobactin, rufomycin, telomycin, lassomycin, ecumicin and hunanamycin.
This PhD project is suitable for applicants with a background and practical experience in organic synthesis. In the course of the project applicants will be trained in additional aspects such as chemical biology and medicinal chemistry. Upon completion of the PhD, you will be qualified for an independent science-based career in academia or industry. The references below will give you an idea of our research and you are welcome to contact me for additional information.
The project may be available at an earlier start date of 1 April or 1 July 2017 but should be discussed with the primary supervisor in the first instance.
References
1) Silva Júnior, P. E.; Rezende, L. C. D.; Gimenes, J. P.; Maltarollo, V. G.; Dale, J.; Trossini, G. H. G.; Emery, F. S.; Ganesan, A. Synthesis of Two ‘Heteroaromatic Rings of the Future’ for Applications in Medicinal Chemistry. RSC Adv. 2016, 6, 22777-22780.
2) 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.
3) Hamon, M.; Dickinson, N.; Devineau, A.; Bolien, D.; Tranchant, M.-J.; Taillier, C.; Jabin, I.; Harrowven, D. C.; Whitby, R. J.; Ganesan, A.; Dalla, V. Intra- and Intermolecular Alkylation of N,O-Acetals and pi-Activated Alcohols Catalyzed by in Situ Generated Acid. J. Org. Chem. 2014, 79, 1900-1912.
4) Tortorici, M.; Borrello, M. T.; Tardugno, M.; Chiarelli, L. R.; Pilotto, S.; Ciossani, G.; Vellore, N. A.; Bailey, S. G.; Cowan, J.; O’Connell, M.; Crabb, S. J.; Packham, G.; Mai, A.; Baron, R.; Ganesan, A.; Mattevi, A. Protein Recognition by Short Peptide Reversible Inhibitors of the Chromatin-Modifying LSD1/CoREST Lysine Demethylase. ACS Chem. Biol. 2013, 8, 1677-1682.
5) Shaheen, F.; Rizvi, T. S.; Musharraf, S. G.; Ganesan, A.; Xiao, K.; Townsend, J. B.; Lam, K. S.; Choudhary, M. I. Solid-Phase Total Synthesis of Cherimolacyclopeptide E and Discovery of More Potent Analogues by Alanine Screening. J. Nat. Prod. 2012, 75, 1882-1887.
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