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

Abstract

Members of the soil-dwelling prokaryotic genus Streptomyces produce many secondary metabolites, including antibiotics and anti-tumour agents. Their formation is coupled with the onset of development, which is 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 antibiotic pathway-specific activators through the pleiotropic transcriptional repressor DasR, the regulon of which also includes all N-acetylglucosamine-related catabolic genes. The results allowed us to devise a new strategy for activating pathways for secondary metabolite biosynthesis. Such 'cryptic' pathways are abundant in actinomycete genomes, thereby offering new prospects in the fight against multiple drug-resistant pathogens and cancers.

Rare earth elements activate the secondary metabolite–biosynthetic gene clusters in Streptomyces coelicolor A3(2)

“…The mechanism of action, however, remains to be clarified. The present method, together with other methods reported recently, 8,9,12,[22][23][24] may be useful for activating silent genes, eventually leading to the discovery of novel biologically active compounds. Figure 3 Comparative metabolic profiling of the culture extracts.…”

Carbon source regulation of antibiotic production

“…107 This effect depends on the nutritional conditions: under famine (poor) conditions, GlcNAc stimulates development and antibiotic production, whereas under feast (rich) conditions, it blocks development. 108 In nature, under starvation conditions, the most likely source of GlcNAc is the autolytic degradation of the bacterial cell wall, whereas under rich conditions, the most likely source is chitin. Hence, GlcNAc signals the nutritional status of the habitat and controls the process of programmed cell death that coincides with development.…”

Activation of secondary metabolite–biosynthetic gene clusters by generating rsmG mutations in Streptomyces griseus

“…Although a biochemical approach (for example, measurement of in vitro protein synthesis activity) was not Effect of rsmG and rpsL mutations on S. griseus Y Tanaka et al employed in the present study, it is possible that the expression of pathway-specific regulatory genes is governed by higher-order regulatory proteins and expression of such higher-order regulatory proteins may be significantly affected under conditions associated with enhanced metK expression in mutants. The present method, together with other methods reported recently, 6,7,[17][18][19][20] may be useful for activating silent genes, eventually leading to the discovery of novel antibacterial agents. …”