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Genotype: Wildtype (M145E)
Medium: Phosphate-limited (F134)

SEEK ID: https://fairdomhub.org/studies/28

Metabolism of Streptomyces coelicolor (SysMO STREAM)

Projects: STREAM, SYSTERACT

Jay Moore

Experimentalists: Not specified

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Created: 26th May 2010 at 15:47

Last updated: 2nd Nov 2016 at 09:38

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SYSTERACT

There is an urgent need for novel antibiotics to fight life-threatening infections and to counteract the increasing problem of propagating antibiotic resistance. Recently, new molecular genetic and biochemical tools have provided insight into the enormous unexploited genetic pool of environmental microbial biodiversity for new antibiotic compounds. New tools for more efficiently lifting this hidden treasure are needed to strengthen competitiveness of European industry, as well as for a cost-saving
...

Programme: ERASysAPP

Public web page: https://www.erasysapp.eu/calls/2nd-call/systeract

STREAM

Global metabolic switching in Streptomyces coelicolor

Antibiotics are made during the second phase of growth when there is a transition in metabolism from primary to secondary metabolism. Primary metabolism is growth related and involves all the normal cellular activities associated with cell growth and division. Whereas secondary metabolism is non-growth linked and is non-essential but many important activities occur during this phase which help the bacterium survive.

Programme: SysMO

Public web page: Not specified

Metabolism of Streptomyces coelicolor (SysMO STREAM)
STREAM, SYSTERACT

Antibiotics are made during the second phase of growth when there is a transition in metabolism from primary to secondary metabolism. Primary metabolism is growth related and involves all the normal cellular activities associated with cell growth and division. Whereas secondary metabolism is non-growth linked and is non-essential but many important activities occur during this phase which help the bacterium survive.

One of these activities is antibiotic production and is widespread in streptomycetes
...

Snapshots: No snapshots

proteomics
STREAM, SYSTERACT
No description specified

Contributor: Jay Moore

Assay type: Proteomics

Technology type: Gas Chromatography Mass Spectrometry

Snapshots: No snapshots

metabolomics
STREAM, SYSTERACT
No description specified

Contributor: Jay Moore

Assay type: Metabolite Profiling

Technology type: Gas Chromatography Mass Spectrometry

Snapshots: No snapshots

transcriptomics
STREAM, SYSTERACT
No description specified

Contributor: Jay Moore

Assay type: Transcriptomics

Technology type: Custom Array

Snapshots: No snapshots

Online/offline measurements
STREAM, SYSTERACT
No description specified

Contributor: Jay Moore

Assay type: Experimental Assay Type

Technology type: Technology Type

Snapshots: No snapshots

Fermentor 199 cultivation data
STREAM
No description specified

Creators: Trond Ellingsen, Øyvind Jakobsen, Per Bruheim, Håvard Sletta, Anders Øverby, Sven Even Borgos, Sunniva Hoel, Alexander Wentzel

Contributor: Jay Moore

Fermentor 199 transcriptomics
STREAM
No description specified

Creators: Jay Moore, Juan-Francisco Martin, Antonio Rodríguez-García, Trond Ellingsen, Øyvind Jakobsen, Per Bruheim, Håvard Sletta, Anders Øverby, Sven Even Borgos, Sunniva Hoel, Alexander Wentzel, Maggie Smith, Louise Thomas, Eriko Takano, Lubbert Dijkhuizen, Rainer Breitling, M. Tauqeer Alam, Anthony Palathingal, R Jansen, Maria Elena Merlo, Morris Swertz, Preben Krabben, Kay Nieselt, Wolfgang Wohlleben, Jens Reuther, David Hodgson, David Rand, David Wild, Elizabeth Wellington, Gregory Challis, Nigel Burroughs, Walid Omara, William Gaze, Brent Kiernan, Roxane Legaie

Contributor: Jay Moore

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3 hidden items
Spore batch generation
STREAM
No description specified

Creators: Trond Ellingsen, Øyvind Jakobsen, Per Bruheim, Håvard Sletta, Anders Øverby, Sven Even Borgos, Sunniva Hoel, Alexander Wentzel

Contributor: Jay Moore

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Metabolome extraction
STREAM
No description specified

Creators: Trond Ellingsen, Øyvind Jakobsen, Per Bruheim, Håvard Sletta, Anders Øverby, Sven Even Borgos, Sunniva Hoel, Alexander Wentzel

Contributor: Jay Moore

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MCF derivatization
STREAM
No description specified

Creators: Trond Ellingsen, Øyvind Jakobsen, Per Bruheim, Håvard Sletta, Anders Øverby, Sven Even Borgos, Sunniva Hoel, Alexander Wentzel

Contributor: Jay Moore

Contamination test of Streptomyces coelicolor culture
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No description specified

Creators: Per Bruheim, Trond Ellingsen, Sunniva Hoel, Øyvind Jakobsen, Håvard Sletta, Alexander Wentzel, Anders Øverby, Strøm, A

Contributor: Jay Moore

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Generation of cell material from Streptomyces coelicolor culture for metabolome analysis
STREAM
No description specified

Creators: Per Bruheim, Trond Ellingsen, Sunniva Hoel, Øyvind Jakobsen, Håvard Sletta, Alexander Wentzel, Anders Øverby, Strøm, A

Contributor: Jay Moore

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Generation of cell material from Streptomyces coelicolor culture for transcriptome analysis
STREAM
No description specified

Creators: Per Bruheim, Trond Ellingsen, Sunniva Hoel, Øyvind Jakobsen, Håvard Sletta, Alexander Wentzel, Anders Øverby, Strøm, A

Contributor: Jay Moore

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Generation of cell material from Streptomyces coelicolor culture for proteome analysis
STREAM
No description specified

Creators: Per Bruheim, Trond Ellingsen, Sunniva Hoel, Øyvind Jakobsen, Håvard Sletta, Alexander Wentzel, Anders Øverby, Strøm, A

Contributor: Jay Moore

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Cell dry weight (CDW) determination of Streptomyces coelicolor culture
STREAM
No description specified

Creators: Per Bruheim, Trond Ellingsen, Sunniva Hoel, Øyvind Jakobsen, Håvard Sletta, Alexander Wentzel, Anders Øverby, Strøm, A

Contributor: Jay Moore

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Sampling from Streptomyces coelicolor culture for subsequent offline analyses
STREAM
No description specified

Creators: Per Bruheim, Trond Ellingsen, Sunniva Hoel, Øyvind Jakobsen, Håvard Sletta, Alexander Wentzel, Anders Øverby, Strøm, A

Contributor: Jay Moore

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Preparation of inoculum for Streptomyces coelicolor cultivation
STREAM
No description specified

Creators: Per Bruheim, Trond Ellingsen, Sunniva Hoel, Øyvind Jakobsen, Håvard Sletta, Alexander Wentzel, Anders Øverby, Strøm, A

Contributor: Jay Moore

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1 hidden item
Optimized submerged batch fermentation strategy for systems scale studies of metabolic switching in Streptomyces coelicolor A3(2)
STREAM

Abstract (Expand)

BACKGROUND: Systems biology approaches to study metabolic switching in Streptomyces coelicolor A3(2) depend on cultivation conditions ensuring high reproducibility and distinct phases of culture growth … and secondary metabolite production. In addition, biomass concentrations must be sufficiently high to allow for extensive time-series sampling before occurrence of a given nutrient depletion for transition triggering. The present study describes for the first time the development of a dedicated optimized submerged batch fermentation strategy as the basis for highly time-resolved systems biology studies of metabolic switching in S. coelicolor A3(2). RESULTS: By a step-wise approach, cultivation conditions and two fully defined cultivation media were developed and evaluated using strain M145 of S. coelicolor A3(2), providing a high degree of cultivation reproducibility and enabling reliable studies of the effect of phosphate depletion and L-glutamate depletion on the metabolic transition to antibiotic production phase. Interestingly, both of the two carbon sources provided, D-glucose and L-glutamate, were found to be necessary in order to maintain high growth rates and prevent secondary metabolite production before nutrient depletion. Comparative analysis of batch cultivations with (i) both L-glutamate and D-glucose in excess, (ii) L-glutamate depletion and D-glucose in excess, (iii) L-glutamate as the sole source of carbon and (iv) D-glucose as the sole source of carbon, reveal a complex interplay of the two carbon sources in the bacterium's central carbon metabolism. CONCLUSIONS: The present study presents for the first time a dedicated cultivation strategy fulfilling the requirements for systems biology studies of metabolic switching in S. coelicolor A3(2). Key results from labelling and cultivation experiments on either or both of the two carbon sources provided indicate that in the presence of D-glucose, L-glutamate was the preferred carbon source, while D-glucose alone appeared incapable of maintaining culture growth, likely due to a metabolic bottleneck at the oxidation of pyruvate to acetyl-CoA.

Authors: A. Wentzel, P. Bruheim, A. Overby, O. M. Jakobsen, H. Sletta, W. A. Omara, D. A. Hodgson, T. E. Ellingsen

Date Published: 9th Jun 2012

Journal: BMC Syst Biol

Extracting regulator activity profiles by integration of de novo motifs and expression data: characterizing key regulators of nutrient depletion responses in Streptomyces coelicolor
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Abstract (Expand)

Determining transcriptional regulator activities is a major focus of systems biology, providing key insight into regulatory mechanisms and co-regulators. For organisms such as Escherichia coli, … transcriptional regulator binding site data can be integrated with expression data to infer transcriptional regulator activities. However, for most organisms there is only sparse data on their transcriptional regulators, while their associated binding motifs are largely unknown. Here, we address the challenge of inferring activities of unknown regulators by generating de novo (binding) motifs and integrating with expression data. We identify a number of key regulators active in the metabolic switch, including PhoP with its associated directed repeat PHO box, candidate motifs for two SARPs, a CRP family regulator, an iron response regulator and that for LexA. Experimental validation for some of our predictions was obtained using gel-shift assays. Our analysis is applicable to any organism for which there is a reasonable amount of complementary expression data and for which motifs (either over represented or evolutionary conserved) can be identified in the genome.

Authors: M. Iqbal, Y. Mast, R. Amin, D. A. Hodgson, W. Wohlleben, N. J. Burroughs

Date Published: 13th Mar 2012

Journal: Nucleic Acids Res

Intracellular Metabolite Pool Changes in Response to Nutrient Depletion Induced Metabolic Switching in Streptomyces coelicolor
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Abstract (Expand)

A metabolite profiling study of the antibiotic producing bacterium Streptomyces coelicolor A3(2) has been performed. The aim of this study was to monitor intracellular metabolite pool changes occurring … as strains of S. coelicolor react to nutrient depletion with metabolic re-modeling, so-called metabolic switching, and transition from growth to secondary metabolite production phase. Two different culture media were applied, providing depletion of the key nutrients phosphate and L-glutamate, respectively, as the triggers for metabolic switching. Targeted GC-MS and LC-MS methods were employed to quantify important primary metabolite groups like amino acids, organic acids, sugar phosphates and other phosphorylated metabolites, and nucleotides in time-course samples withdrawn from fully-controlled batch fermentations. A general decline, starting already in the early growth phase, was observed for nucleotide pools and phosphorylated metabolite pools for both the phosphate and glutamate limited cultures. The change in amino acid and organic acid pools were more scattered, especially in the phosphate limited situation while a general decrease in amino acid and non-amino organic acid pools was observed in the L-glutamate limited situation. A phoP deletion mutant showed basically the same metabolite pool changes as the wild-type strain M145 when cultivated on phosphate limited medium. This implies that the inactivation of the phoP gene has only little effect on the detected metabolite levels in the cell. The energy charge was found to be relatively constant during growth, transition and secondary metabolite production phase. The results of this study and the employed targeted metabolite profiling methodology are directly relevant for the evaluation of precursor metabolite and energy supply for both natural and heterologous production of secondary metabolites in S. coelicolor.

Authors: A. Wentzel, H. Sletta, T. E. Ellingsen, P. Bruheim

Date Published: 2012

Journal: Metabolites

Metabolic switches and adaptations deduced from the proteomes of Streptomyces coelicolor wild type and phoP mutant grown in batch culture
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Abstract (Expand)

Bacteria in the genus Streptomyces are soil-dwelling oligotrophs and important producers of secondary metabolites. Previously, we showed that global messenger RNA expression was subject to a series of … metabolic and regulatory switches during the lifetime of a fermentor batch culture of Streptomyces coelicolor M145. Here we analyze the proteome from eight time points from the same fermentor culture and, because phosphate availability is an important regulator of secondary metabolite production, compare this to the proteome of a similar time course from an S. coelicolor mutant, INB201 (DeltaphoP), defective in the control of phosphate utilization. The proteomes provide a detailed view of enzymes involved in central carbon and nitrogen metabolism. Trends in protein expression over the time courses were deduced from a protein abundance index, which also revealed the importance of stress pathway proteins in both cultures. As expected, the DeltaphoP mutant was deficient in expression of PhoP-dependent genes, and several putatively compensatory metabolic and regulatory pathways for phosphate scavenging were detected. Notably there is a succession of switches that coordinately induce the production of enzymes for five different secondary metabolite biosynthesis pathways over the course of the batch cultures.

Authors: L. Thomas, D. A. Hodgson, A. Wentzel, K. Nieselt, T. E. Ellingsen, J. Moore, E. R. Morrissey, R. Legaie, W. Wohlleben, A. Rodriguez-Garcia, J. F. Martin, N. J. Burroughs, E. M. Wellington, M. C. Smith

Date Published: 8th Dec 2011

Journal: Mol Cell Proteomics

A technical platform for generating reproducible expression data from Streptomyces coelicolor batch cultivations
STREAM

Abstract (Expand)

Streptomyces coelicolor, the model species of the genus Streptomyces, presents a complex life cycle of successive morphological and biochemical changes involving the formation of substrate and aerial … mycelium, sporulation and the production of antibiotics. The switch from primary to secondary metabolism can be triggered by nutrient starvation and is of particular interest as some of the secondary metabolites produced by related Streptomycetes are commercially relevant. To understand these events on a molecular basis, a reliable technical platform encompassing reproducible fermentation as well as generation of coherent transcriptomic data is required. Here, we investigate the technical basis of a previous study as reported by Nieselt et al. (BMC Genomics 11:10, 2010) in more detail, based on the same samples and focusing on the validation of the custom-designed microarray as well as on the reproducibility of the data generated from biological replicates. We show that the protocols developed result in highly coherent transcriptomic measurements. Furthermore, we use the data to predict chromosomal gene clusters, extending previously known clusters as well as predicting interesting new clusters with consistent functional annotations.

Authors: F. Battke, A. Herbig, A. Wentzel, O. M. Jakobsen, M. Bonin, D. A. Hodgson, W. Wohlleben, T. E. Ellingsen, K. Nieselt

Date Published: 25th Mar 2011

Journal: Adv Exp Med Biol

The dynamic architecture of the metabolic switch in Streptomyces coelicolor
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Abstract (Expand)

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: Kay Nieselt, Florian Battke, Alexander Herbig, Per Bruheim, Alexander Wentzel, Øyvind Jakobsen, Håvard Sletta, M. Tauqeer Alam, Maria Elena Merlo, Jay Moore, Walid Omara, Edward R Morrissey, Miguel A Juarez-Hermosillo, Antonio Rodríguez-García, Merle Nentwich, Louise Thomas, Mudassar Iqbal, Roxane Legaie, William Gaze, Gregory Challis, R Jansen, Lubbert Dijkhuizen, David Rand, David Wild, Michael Bonin, Jens Reuther, Wolfgang Wohlleben, Maggie Smith, Nigel Burroughs, Juan-Francisco Martin, David Hodgson, Eriko Takano, Rainer Breitling, Trond Ellingsen, Elizabeth Wellington

Date Published: 28th May 2009

Journal: BMC Genomics

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