Streptomyces bacteria are the source of nearly half of our clinically used natural antibiotics. Production of bioactive compounds is usually linked to complex networks of signal-sensing proteins that regulate genes. How do these complex systems come together? Recent advances in molecular biology provide the tools to uncover the detailed mechanisms that underlie the evolution of vast regulatory networks that create complex biological systems.
This project will examine the molecular mechanisms that allow two regulatory proteins that arose from a single duplicated gene in Streptomyces coelicolor to regulate distinct and critical components of sporulation, quorum-sensing, and antibiotic synthesis.
By using a combination of ancestral sequence reconstruction and experimental protein evolution, this project will explore how these proteins took up new regulatory roles, resulting in the current system. Furthermore, we will recreate the intermediate steps along this evolutionary trajectory, in order to discover how the functions of these essential genes were rapidly separated by evolution. Finally, using a system of experimental laboratory evolution, we will alter these proteins to more effectively regulate their targets in an attempt to accelerate antibiotic production.
Ultimately, we will map out some of the ways in which new regulatory proteins can evolve through duplication and modification of genes for existing regulatory proteins. We will also aim to provide new mechanisms that can accelerate the production of antibiotics for clinical use.