Feast or famine: the global regulator DasR links nutrient stress to antibiotic production by Streptomyces

Members of the soil-dwelling prokaryotic genus Streptomyces produce a wealth of secondary metabolites, including antibiotics and anti-tumour agents. Their formation is intimately coupled with the onset of development, triggered by the nutrient status of the habitat. We propose the first complete signalling cascade from nutrient sensing to development and antibiotic biosynthesis. We show that a high concentration of N-acetylglucosamine - perhaps mimicking the accumulation of N-acetylglucosamine after autolytic degradation of the vegetative mycelium - is a major checkpoint for the onset of secondary metabolism. The response is transmitted to the antibiotic pathway-specific activators via the pleiotropic transcriptional repressor DasR, whose regulon also includes all N-acetylglucosamine-related catabolic genes. The results have led to a new strategy for activating “cryptic” pathways for secondary metabolite biosynthesis, which are abundant in actinomycete genomes, thereby offering new prospects in the fight against multiply drug resistant pathogens and cancers.