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Metabolic modeling and analysis of the metabolic switch in Streptomyces coelicolor

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Background The transition from exponential to stationary phase in Streptomyces coelicolor is accompanied by a major metabolic switch and results in a strong activation of secondary metabolism. Here we … have explored the underlying reorganization of the metabolome by combining computational predictions based on constraint-based modeling and detailed transcriptomics time course observations. Results We reconstructed the stoichiometric matrix of S. coelicolor, including the major antibiotic biosynthesis pathways, and performed flux balance analysis to predict flux changes that occur when the cell switches from biomass to antibiotic production. We defined the model input based on observed fermenter culture data and used a dynamically varying objective function to represent the metabolic switch. The predicted fluxes of many genes show highly significant correlation to the time series of the corresponding gene expression data. Individual mispredictions identify novel links between antibiotic production and primary metabolism. Conclusion Our results show the usefulness of constraint-based modeling for providing a detailed interpretation of time course gene expression data. Other Sections▼

Authors: , , The STREAM Consortium (stream), , , ,

Date Published: 2010

Publication Type: Not specified

The dynamic architecture of the metabolic switch in Streptomyces coelicolor

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BACKGROUND: During the lifetime of a fermenter culture, the soil bacterium S. coelicolor undergoes a major metabolic switch from exponential growth to antibiotic production. We have studied gene … expression patterns during this switch, using a specifically designed Affymetrix genechip and a high-resolution time-series of fermenter-grown samples. RESULTS: Surprisingly, we find that the metabolic switch actually consists of multiple finely orchestrated switching events. Strongly coherent clusters of genes show drastic changes in gene expression already many hours before the classically defined transition phase where the switch from primary to secondary metabolism was expected. The main switch in gene expression takes only 2 hours, and changes in antibiotic biosynthesis genes are delayed relative to the metabolic rearrangements. Furthermore, global variation in morphogenesis genes indicates an involvement of cell differentiation pathways in the decision phase leading up to the commitment to antibiotic biosynthesis. CONCLUSIONS: Our study provides the first detailed insights into the complex sequence of early regulatory events during and preceding the major metabolic switch in S. coelicolor, which will form the starting point for future attempts at engineering antibiotic production in a biotechnological setting.

Authors: , Florian Battke, Alexander Herbig, , , , , , , , , Edward R Morrissey, Miguel A Juarez-Hermosillo, , Merle Nentwich, , Mudassar Iqbal, , , , , , , , Michael Bonin, , , , , , , , , ,

Date Published: 28th May 2009

Publication Type: Not specified

Chapter 6. Regulation of antibiotic production by bacterial hormones

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Antibiotic production is regulated by numerous signals, including the so-called bacterial hormones found in antibiotic producing organisms such as Streptomyces. These signals, the gamma-butyrolactones, … are produced in very small quantities, which has hindered their structural elucidation and made it difficult to assess whether they are being produced. In this chapter, we describe a rapid small-scale extraction method from either solid or liquid cultures in scales of one plate or 50 ml of medium. Also described is a bioassay to detect the gamma-butyrolactones by determining either the production of pigmented antibiotic of Streptomyces coelicolor or kanamycin resistant growth on addition of the gamma-butyrolactones. We also describe some insights into the identification of the gamma-butyrolactone receptor and its targets and also the gel retardation conditions with three differently labeled probes.

Authors: Nai-Hua Hsiao, Marco Gottelt,

Date Published: 21st Apr 2009

Publication Type: Not specified

A bistable gene switch for antibiotic biosynthesis: the butyrolactone regulon in Streptomyces coelicolor

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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 gamma-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 gamma-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.

Authors: Sarika Mehra, Salim Charaniya, , Wei-Shou Hu

Date Published: 2nd May 2008

Publication Type: Not specified

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