Abstract
Antibiotic production is coordinated in the Streptomyces coelicolor population through the use of diffusible signaling molecules of the γ-butyrolactone (GBL) family. The GBL regulatory system involves a small, and not completely defined two-gene network which governs a potentially bi-stable switch between the “on” and “off” states of antibiotic production. The use of this circuit as a tool for synthetic biology has been hampered by a lack of mechanistic understanding of its functionality. We here present the creation and analysis of a versatile and adaptable ensemble model of the Streptomyces GBL system (detailed information on all model mechanisms and parameters is documented in http://www.systemsbiology.ls.manchester.ac.uk/wiki/index.php/Main_Page). We use the model to explore a range of previously proposed mechanistic hypotheses, including transcriptional interference, antisense RNA interactions between the mRNAs of the two genes, and various alternative regulatory activities. Our results suggest that transcriptional interference alone is not sufficient to explain the system’s behavior. Instead, antisense RNA interactions seem to be the system's driving force, combined with an aggressive scbR promoter. The computational model can be used to further challenge and refine our understanding of the system’s activity and guide future experimentation.
Highlights
The core aim of synthetic biology is the design and engineering of complex biological systems with functionalities that do not exist in nature
Streptomyces species are Gram-positive soil-dwelling bacteria, which are known as a prolific source of secondary metabolites, such as antibiotics
Antibiotic production is coordinated in the bacterial population through the use of diffusible signalling molecules of the γ-butyrolactone (GBL) family
Summary
The core aim of synthetic biology is the design and engineering of complex biological systems with functionalities that do not exist in nature. As the antibiotic compounds can be toxic even to the producing strains, their biosynthesis needs to be carefully regulated in a population This is achieved via the SCB1γbutyrolactones, a group of signaling molecules associated with the regulation of antibiotic production and some aspects of bacterial morphology. ScbR belongs to the TetR family of repressors and inhibits its own transcription, as well as the transcription of the divergently encoded ScbA, which is the synthase of the butyrolactone signaling molecule SCB1. It represses cpkO, a regulatory gene for the CPK antibiotic biosynthesis gene cluster.[10, 11] SCB1 binds to ScbR, effectively deactivating the DNA binding activity and leading to the further production of butyrolactones. The CPK cluster is activated, leading to the production of antibiotics
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