A Bistable Gene Switch for Antibiotic Biosynthesis: The Butyrolactone Regulon in Streptomyces coelicolor

Abstract

Many microorganisms, including bacteria of the class Streptomycetes, produce various secondary metabolites including antibiotics to gain a competitive advantage in their natural habitat. The production of these compounds is highly coordinated in a population to expedite accumulation to an effective concentration. Furthermore, as antibiotics are often toxic even to their producers, a coordinated production allows microbes to first arm themselves with a defense mechanism to resist their own antibiotics before production commences. One possible mechanism of coordination among individuals is through the production of signaling molecules. The γ-butyrolactone system in Streptomyces coelicolor is a model of such a signaling system for secondary metabolite production. The accumulation of these signaling molecules triggers antibiotic production in the population. A pair of repressor-amplifier proteins encoded by scbA and scbR mediates the production and action of one particular γ-butyrolactone, SCB1. Based on the proposed interactions of scbA and scbR, a mathematical model was constructed and used to explore the ability of this system to act as a robust genetic switch. Stability analysis shows that the butyrolactone system exhibits bistability and, in response to a threshold SCB1 concentration, can switch from an OFF state to an ON state corresponding to the activation of genes in the cryptic type I polyketide synthase gene cluster, which are responsible for production of the hypothetical polyketide. The switching time is inversely related to the inducer concentration above the threshold, such that short pulses of low inducer concentration cannot switch on the system, suggesting its possible role in noise filtering. In contrast, secondary metabolite production can be triggered rapidly in a population of cells producing the butyrolactone signal due to the presence of an amplification loop in the system. S. coelicolor was perturbed experimentally by varying concentrations of SCB1, and the model simulations match the experimental data well. Deciphering the complexity of this butyrolactone switch will provide valuable insights into how robust and efficient systems can be designed using “simple” two-protein networks.

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

“…An alternative and perhaps simpler interpretation of the same data is possible, in which the only role of ScbA is to catalyze SCB biosynthesis and the regulatory effects are all mediated by the concentration-dependent interplay of SCBs with ScbR (20). Mathematical modeling of the scbAR/cpk system has shown that its autoamplifying nature may amount to a developmental commitment to CPK production, by acting as a bistable switch (46,47). Recently, it was reported that a mutation in scbR leading to the amino acid change R120S had occurred independently in two lines of S. coelicolor, one of them being the fairly frequently used strain M600 (48).…”

Mathematical Modelling of Bacterial Quorum Sensing: A Review

“…See Goryachev (2011) for a review of this particular type of models. Other models in this area are those from Mehra et al (2008), Brown (2010), and Chen et al (2004), which are not included here as they have already been reviewed in Goryachev (2011).…”

Repression of Antibiotic Production and Sporulation inStreptomyces coelicolorby Overexpression of a TetR Family Transcriptional Regulator

“…The best hit found was in the promoter region of scbA, a gene encoding a protein required for ␥-butyrolactone SCB1 biosynthesis (61). The expression of scbA is known to be positively regulated by the divergently located TetR-like regulator ScbR through direct interaction (45,61). ScbR was also shown to negatively regulate its own expression and that of cpkO, a gene encoding the putative pathway-specific transcriptional regulator of the cryptic type I polyketide gene cluster, also through direct interaction (63).…”