Feast or famine: the global regulator DasR links nutrient stress to antibiotic production by Streptomyces.
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.
Rigali
Sébastien
S
Microbial Development, Leiden Institute of Chemistry, Leiden University, PO Box 9502, 2300RA Leiden, The Netherlands.
Titgemeyer
Fritz
F
Barends
Sharief
S
Mulder
Suzanne
S
Thomae
Andreas W
AW
Hopwood
David A
DA
van Wezel
Gilles P
GP
D000117:Acetylglucosamine / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D001426:Bacterial Proteins / Q000378:metabolism*; D003470:Culture Media; D015398:Signal Transduction; D048372:Streptomyces coelicolor / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003470:Culture Media; D000117:Acetylglucosamine