My research focuses on understanding the regulation of metabolism in microorganisms with biotechnological applications using functional genomics and systems biology. 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. Recent examples of this have been an exploration of the bottlenecks in heterologous protein production in chemostat cultures of the yeast Pichia pastoris using RNA-seq analysis, a study of desiccation tolerance in Saccharomyces cerevisiae, and analysis of the regulation of antibiotic biosynthesis in Streptomyces spp. 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 S. 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 contribute to the resistance towards antibiotics in bacteria. 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. We use functional genomics approaches to try to understand the global responses of bacteria to antibiotic exposure. The ultimate motivation is to obtain an integrated understanding of how bacteria can adapt to survive in the presence of antibiotic treatments and thereby to suggest opportunities for improving activity via rational redesign, or by synergisticly targeting more than one important cellular process.
Key recent publications:
- Hesketh, A., Deery, M.J., Hong, H-J. (2015) High-resolution mass spectrometry based proteomic analysis of the response to vancomycin-induced cell wall stress in Streptomyces coelicolor A3(2). J. Prot. Res. 14(7): 2915-28. doi: 10.1021/acs.j proteome.5b00242.
- 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. doi: 10.1007/s00253-013-5186-1
- 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.
- 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
- 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.
- 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
Prof. Steve Oliver, Cambridge Systems Biology Centre, University of Cambridge, UK.
Dr Hee-Jeon Hong, Department of Biochemistry, University of Cambridge, UK.
Prof. Luca Guardabassi, Professor in Antimicrobial Resistance and Antibiosis, University of Copenhagen, Denmark.
Dr Douglas Murray, Institute for Advanced Biosciences, Keio University, Japan.