My research interests focus on obtaining an integrated understanding of how microbial cells regulate their growth and metabolism, and how this knowledge can be applied and exploited both for the optimisation of biotechnologically relevant native and engineered metabolic pathways, and for defining and understanding fundamentally important cell processes. I have recently (2010) branched out from working exclusively on antibiotic production and resistance in the prokaryotic Streptomyces species, to also studying growth and metabolism in the model eukaryote Saccharomyces cerevisiae.
Saccharomyces cerevisiae is increasingly being used as a microbial host in biotechnology for research aimed at developing methods for the sustainable production of renewable/carbon-neutral energy sources, and of chemicals of pharmaceutical importance. Such work aims to introduce new metabolic pathways into yeast cells for the production of the desired fuel or chemical product. This essentially hijacks the metabolism of the cell away from its normal processes, and requires it to use its energy resources in a significantly different way. A detailed understanding of the molecular systems which control and balance the supply and use of energy in Saccharomyces cerevisiae will help enable the yields and efficiencies of novel biotechnological processes like these to be optimized, thereby increasing the likelihood that they can become implemented and commercially viable.
Current research is focused on exploring the role of intracellular purine nucleotide pool composition in keeping metabolic activity in tune with nutrient availability. To accomplish this we are using the regulated expression of bacterial genes that encode enzymes which use ATP or GTP as substrates to induce controlled in vivo changes in purine nucleotide concentrations that are independent of nutrient supply. The consequences of the induced changes on cellular metabolism are being characterized using biochemical, functional genomics, and systems biology approaches.
Key recent publications:
- 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
- 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
- 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
- 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.x
- Bibb, M., & Hesketh, A. (2009). Chapter 4. Analyzing the regulation of antibiotic production in streptomycetes. Methods Enzymol, 458, 93-116. doi:10.1016/S0076-6879(09)04804-6
- 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