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Andy Hesketh

I aim to work at the interface of Systems Biology and Synthetic Biology, studying microorganisms with biotechnological applications and using Systems Biology approaches to inform, optimise and achieve goals in Synthetic Biology. A recent example of this was an exploration of the bottlenecks in heterologous protein production in chemostat cultures of the yeast Pichia pastoris using RNA-seq analysis. I have a long running interest in how microbial cells regulate their metabolism in response to their nutritional status, and the implications that this has for the efficiency of both natural and engineered metabolic processes. I am currently researching the extent to which the monitoring of cellular energy status, via fluctuations in the composition of intracellular purine nucleotide concentrations, influences the regulation of growth and metabolism in the model microbial eukaryote Saccharomyces cerevisiae. S. cerevisiae has a proven track record as an industrial host for the production of a diverse range of chemicals, but the integration of engineered pathways with host metabolism at the level of cellular energy status has remained poorly defined. We are integrating SGA screening of the yeast deletion mutant collection with transcriptomics analysis of engineered strains grown under controlled nutritional conditions in chemostats to begin to increase our understanding of this area.

I also have an active interest in understanding the complex regulatory networks that govern the production and resistance towards antibiotics of actinomycete origin (and in the analysis of transcriptome data of any origin!). Antibiotics from natural sources are a vital, but potentially diminishing, resource in the fight against infectious disease, and such knowledge will be fundamental in being able to continue to exploit their full potential.

Key recent publications:

  1. Hesketh, A.R., Castrillo, J.I., Sawyer, T., Archer, D.B., Oliver SG. (2013) Investigating the physiological response of Pichia (Komagataella) pastoris GS115 to the heterologous expression of misfolded proteins using chemostat cultures. Appl Microbiol Biotechnol. 97: 9747-9762.

  2. Hesketh, A. and Hong, H-J. (2013) Comparative and functional genomics as tools for understanding vancomycin resistance in bacteria. Book chapter in "Vancomycin: Biosynthesis, Clinical Uses and Adverse Effects." Nova Science Publishers Inc, New York, USA.

  3. Hesketh, A., Hill, C., Mokhtar, J., Novotna, G., Tran, N., Bibb, M., & Hong, H. J. (2011). Genome-wide dynamics of a bacterial response to antibiotics that target the cell envelope. BMC Genomics, 12, 226. doi:10.1186/1471-2164-12-226

  4. Ratnakumar, S., Hesketh, A., Gkargkas, K., Wilson, M., Rash, B. M., Hayes, A., Tunnacliffe, A. & Oliver, S. G. (2011). Phenomic and transcriptomic analyses reveal that autophagy plays a major role in desiccation tolerance in Saccharomyces cerevisiae. Mol Biosyst, 7(1), 139-149. doi:10.1039/c0mb00114g

  5. Wyszynski, F. J., Hesketh, A. R., Bibb, M. J., & Davis, B. G. (2010). Dissecting tunicamycin biosynthesis by genome mining: cloning and heterologous expression of a minimal gene cluster. CHEM SCI, 1(5), 581-589. doi:10.1039/c0sc00325e

  6. Hesketh, A., Kock, H., Mootien, S., & Bibb, M. (2009). The role of absC, a novel regulatory gene for secondary metabolism, in zinc-dependent antibiotic production in Streptomyces coelicolor A3(2). Mol Microbiol, 74(6), 1427-1444. doi:10.1111/j.1365-2958.2009.06941.

  7. Hesketh, A., Chen, W. J., Ryding, J., Chang, S., & Bibb, M. (2007). The global role of ppGpp synthesis in morphological differentiation and antibiotic production in Streptomyces coelicolor A3(2). Genome Biol, 8(8), R161. doi:10.1186/gb-2007-8-8-r161