The gamma-butyrolactone receptors ScbR and AtrA form a quorum sensing switch between coelimycin and actinorhodin synthesis inStreptomyces coelicolorA3(2)

ABSTRACT Background Quorum sensing enables gene expression regulation in response to changes in cell population density and controls diverse processes, such as biofilm formation, virulence and antibiotic production, in bacteria. In one of the largest, soil-dominant phylum Actinobacteria , cell-to-cell communication occurs through the small, membrane-diffusible signalling molecules gamma-butyrolactones (GBLs). Their actions are exerted through receptor proteins that also act as response regulators in a one-component system manner. With only a few GBL systems characterized, most of them come from the large, antibiotic-producer genus Streptomyces . In the model organism Streptomyces coelicolor A3(2), two GBL receptors, ScbR and SlbR, which are both antibiotic production repressors, have been reported so far. Results In this work, we identified a new GBL receptor protein, the conserved and pleiotropic regulator AtrA, which has an activating mode of action. Moreover, we elucidated the precise mechanism by which it controls the production of the antibiotic actinorhodin through the actinorhodin biosynthetic gene cluster activator ActII-orf4. GBL binding to AtrA prevents its binding to the promoter of the actII-orf4 gene, thereby disabling its transcription, while at the same time, GBL binding to ScbR causes coelimycin antibiotic synthesis derepression. Conclusions The opposite modes of action of ScbR (repressor) and AtrA (activator) have opposite effects upon GBL binding, activating coelimycin and blocking actinorhodin production at the same time. This phenomenon constitutes an elegant regulatory mechanism that ensures that coelimycin and actinorhodin production are mutually exclusive. These findings also suggest that quorum sensing must be taken into account when designing efficient antibiotic production processes and can be manipulated to ensure both better yield and specificity.