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 firstname.lastname@example.org http://synbiochem.co.uk/