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Control of antibiotic production through synthetic biology of bacterial hormone signalling


Project Description

There is an urgent need for new antibiotics due to an increase in antibiotic resistance. To produce these essential drugs efficiently in biotechnological systems, we need to have a better understanding of the regulatory mechanisms of antibiotic production.

Small diffusible molecules are known to act as “hormones” controlling antibiotic production in Streptomyces, the most important source of clinically relevant antibiotics. Their complex regulatory cascade involving the synthase and receptor (ScbA/R system) has been elucidated (1,2,3). In this project, we aim to elucidate layers of control in the ScbA/R system and develop this system into a regulatory tool for the engineering of heterologous antibiotic production and other synthetic biology applications (4).

1) Transcriptional control: expression of ScbA/R is controlled by a regulatory design that is unique in bacterial systems (1). This will be investigated using RNAseq and mutational studies, as well as by characterizing the multiple regulatory proteins binding the promoter regions.

2) Translational control: we found that the hormone receptor, ScbR, is modified post-translationally; the effect on enzyme activity and the protein structure of the modified ScbR will be analysed.

3) We have developed a computational model of ScbA/R signalling (ms. submitted), which will be used to integrate the data from steps 1 and 2.

4) The ScbA/R system has been recently expressed in E. coli, as an orthogonal regulatory circuit (5). To expand the versatility of this new tool, we will combine the Streptomyces system with elements from other species, creating new chemical variants of the hormones, using directed evolution to develop the required new receptor proteins.

This project is ideal for bioanalytical, biotechnology and biochemistry students, with a strong interest in synthetic biology and computational analysis and a willingness to learn the interdisciplinary skills required for postgenomic data generation and analysis in molecular biology.

Contact for further Information
Eriko Takano

http://synbiochem.co.uk/

Funding Notes

Applications are invited from self-funded students. For UK/EU tuition fees are £15,500 and International are £30,500 for 2019/20 academic year.

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or the overseas equivalent) in the related area / subject. Candidates with experience in molecular biology, biochemistry, and or bioanalytics with an interest in computational analysis are encouraged to apply.

References

1) Biarnes-Carrera M, Breitling R, Takano E. Butyrolactone signalling circuits for synthetic biology. Curr. Opin. Chem. Biol. (2015) 28:91-98.
2) D’Alia D, Eggle D, Nieselt K, Hu WH, Breitling R, and Takano E. Deletion of the signaling molecule synthase ScbA has pleiotropic effects on secondary metabolite biosynthesis, morphological differentiation and primary metabolism in Streptomyces coelicolor A3(2) Microb Biotech (2010) 4:239–251.
3) Hsiao NH, Nakayama S, Merlo ME, de Vries M, Bunet R, Kitani, S., Nihira T, and Takano E. Analysis of two additional signalling molecules in Streptomyces coelicolor and development of a butyrolactone-specific reporter system. Chem Biol. (2009) 16:951–960.
4) Cummings M, Peters AD, Whitehead GFS, Menon BRK, Micklefield J, Webb SJ, Takano E. Assembling a plug-and-play production line for combinatorial biosynthesis of aromatic polyketides in Escherichia coli. PLOS Biol (2019) 17 e3000347.4)
5) Biarnes M, Lee CK, Nihira T, Breitling R, Takano E. Orthogonal regulatory circuits for E. coli based on the γ-butyrolactone system of Streptomyces coelicolor. ACS Synth Biol (2018) 7:1043-1055.

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