Cascades and Networks of Regulatory Genes That Control Antibiotic Biosynthesis

Martı́n, Juan F.; Liras, Paloma

doi:10.1007/978-94-007-5055-5_6

Cited by 36 publications

(23 citation statements)

References 129 publications

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“…Strains were grown in media containing limited or proficient amount of phosphate, conditions known to promote and repress antibiotic production, respectively 23–25 . Pi consumption, as well as intracellular concentrations of free phosphate, polyP, ATP and ADP were measured in these two conditions.…”

Section: Introductionmentioning

confidence: 99%

Strong antibiotic production is correlated with highly active oxidative metabolism in Streptomyces coelicolor M145

Esnault

Dulermo

Smirnov

et al. 2017

Sci Rep

125

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The Streptomyces genus is well known for its ability to produce bio-active secondary metabolites of great medical interest. However, the metabolic features accompanying these bio-productions remain to be defined. In this study, the comparison of related model strains producing differing levels of actinorhoddin (ACT), showed that S. lividans, a weak producer, had high TriAcylGlycerol (TAG) content indicative of a glycolytic metabolism. In contrast, the strong producer, S. coelicolor, was characterized by low TAG content, active consumption of its polyphosphate (PolyP) stores and extremely high ATP/ADP ratios. This indicated highly active oxidative metabolism that was correlated with induction of ACT biosynthesis. Interestingly, in conditions of phosphate limitation, the ppk mutant had TAG content and ACT production levels intermediary between those of S. lividans and S. coelicolor. This strain was characterized by high ADP levels indicating that Ppk was acting as an Adenosine Di Phosphate Kinase. Its absence resulted in energetic stress that is proposed to trigger an activation of oxidative metabolism to restore its energetic balance. This process, which is correlated with ACT biosynthesis, requires acetylCoA to fuel the Krebs cycle and phosphate for ATP generation by the ATP synthase coupled to the respiratory chain, resulting in low TAG and polyP content of the ACT producing strains.

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Section: Introductionmentioning

confidence: 99%

Strong antibiotic production is correlated with highly active oxidative metabolism in Streptomyces coelicolor M145

Esnault

Dulermo

Smirnov

et al. 2017

Sci Rep

125

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“…This article builds on three excellent broadly based reviews on the regulation of antibiotic production in Streptomyces (18)(19)(20). Other wide-ranging reviews of the topic have also appeared recently (21,22).…”

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confidence: 99%

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

Liu

Chater

Chandra

et al. 2013

Microbiol Mol Biol Rev

598

536

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SUMMARY Streptomycetes are the most abundant source of antibiotics. Typically, each species produces several antibiotics, with the profile being species specific. Streptomyces coelicolor , the model species, produces at least five different antibiotics. We review the regulation of antibiotic biosynthesis in S. coelicolor and other, nonmodel streptomycetes in the light of recent studies. The biosynthesis of each antibiotic is specified by a large gene cluster, usually including regulatory genes (cluster-situated regulators [CSRs]). These are the main point of connection with a plethora of generally conserved regulatory systems that monitor the organism's physiology, developmental state, population density, and environment to determine the onset and level of production of each antibiotic. Some CSRs may also be sensitive to the levels of different kinds of ligands, including products of the pathway itself, products of other antibiotic pathways in the same organism, and specialized regulatory small molecules such as gamma-butyrolactones. These interactions can result in self-reinforcing feed-forward circuitry and complex cross talk between pathways. The physiological signals and regulatory mechanisms may be of practical importance for the activation of the many cryptic secondary metabolic gene cluster pathways revealed by recent sequencing of numerous Streptomyces genomes.

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“…The biosynthesis of secondary metabolites in actinomycetes is governed by complex regulatory networks involving both global/pleiotropic and pathway-specific regulators (1)(2)(3)(4). A better understanding of these regulatory networks is critically important for strain improvement by metabolic engineering or synthetic biology approaches (1,5).…”

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confidence: 99%

Direct Involvement of the Master Nitrogen Metabolism Regulator GlnR in Antibiotic Biosynthesis in Streptomyces

Zhu

Zheng

et al. 2016

Journal of Biological Chemistry

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Edited by Joel GottesfeldGlnR, an OmpR-like orphan two-component system response regulator, is a master regulator of nitrogen metabolism in the genus Streptomyces. In this work, evidence that GlnR is also directly involved in the regulation of antibiotic biosynthesis is provided. In the model strain Streptomyces coelicolor M145, an in-frame deletion of glnR resulted in markedly increased actinorhodin (ACT) production but reduced undecylprodigiosin (RED) biosynthesis when exposed to R2YE culture medium. Transcriptional analysis coupled with DNA binding studies revealed that GlnR represses ACT but activates RED production directly via the pathway-specific activator genes actII-ORF4 and redZ, respectively. The precise GlnR-binding sites upstream of these two target genes were defined. In addition, the direct involvement of GlnR in antibiotic biosynthesis was further identified in Streptomyces avermitilis, which produces the important anthelmintic agent avermectin. We found that S. avermitilis GlnR (GlnRsav) could stimulate avermectin but repress oligomycin production directly through the respective pathway-specific activator genes, aveR and olmRI/RII. To the best of our knowledge, this report describes the first experimental evidence demonstrating that GlnR regulates antibiotic biosynthesis directly through pathway-specific regulators in Streptomyces. Our results suggest that GlnR-mediated regulation of antibiotic biosynthesis is likely to be universal in streptomycetes. These findings also indicate that GlnR is not only a master nitrogen regulator but also an important controller of secondary metabolism, which may help to balance nitrogen metabolism and antibiotic biosynthesis in streptomycetes.

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Cascades and Networks of Regulatory Genes That Control Antibiotic Biosynthesis

Cited by 36 publications

References 129 publications

Strong antibiotic production is correlated with highly active oxidative metabolism in Streptomyces coelicolor M145

Strong antibiotic production is correlated with highly active oxidative metabolism in Streptomyces coelicolor M145

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

Direct Involvement of the Master Nitrogen Metabolism Regulator GlnR in Antibiotic Biosynthesis in Streptomyces

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