JRG/1: Cyclic di-GMP in the Control of Multicellular Differentiation in Antibiotic-Producing Bacteria Streptomyces

Streptomyces are the most abundant source of clinically important antibiotics and other natural products used in human medicine. The production of these secondary metabolites is temporally and genetically coordinated with a complex developmental life cycle involving growth as vegetative mycelium of branching hyphae and dispersion via spores formed on specialised reproductive structures called aerial hyphae. We have recently discovered that the nucleotide second messenger c-di-GMP, which is produced by GGDEF-domain proteins and degraded by either EAL- or HD-GYP-domain proteins, plays a crucial role in controlling Streptomyces development. We identified the developmental master regulator BldD as a first c-di-GMP effector in the genus Streptomyces and demonstrated that BldD binds a tetrameric form of c-di-GMP, which results in transcription factor dimerisation and effective repression of sporulation genes during vegetative growth. However, our knowledge about c-di-GMP signalling components in Streptomyces is still very limited. The aim of this project is to systematically analyse and characterise in molecular detail the functions and regulatory aspects of all GGDEF, EAL, HD-GYP domain proteins in Streptomyces venezuelae. Altogether, the proposed research aims at finding the mechanism(s) of action of these c-di-GMP signalling components, elucidation of their position(s) in cellular regulatory pathways and uncovering of their physiological role(s). This work will greatly improve our understanding of Streptomyces physiology and c-di-GMP signalling in a new physiological context involving multicellular differentiation and secondary metabolite production and can contribute to a better exploitation of genetic engineering in Streptomyces for the production of antibiotics.