The global role of ppGpp synthesis in morphological differentiation and antibiotic production in Streptomyces coelicolor A3(2)

Hesketh, Andrew; Chen, Wenqiong Joan; Ryding, Jamie; Chang, Sherman; Bibb, Mervyn J.

doi:10.1186/gb-2007-8-8-r161

Cited by 132 publications

(123 citation statements)

References 69 publications

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“…Deletion of the relA gene suppresses antibiotic production, underlining the important role of the stringent response in controlling antibiotic production (380). Indeed, under nitrogen-limiting conditions ppGpp causes a dramatic switch in the physiology of streptomycetes, activating the expression of genes involved in morphological and chemical differentiation, including the production of CDA and actinorhodin, and at the same time repressing genes involved in normal growth (381). The exact mechanism by which ppGpp acts upon such a wide range of genes remains to be elucidated.…”

Section: Correlation Between Growth and Antibiotic Productionmentioning

confidence: 99%

Taxonomy, Physiology, and Natural Products of Actinobacteria

Barka

Vatsa

Sanchez

et al. 2016

Microbiol Mol Biol Rev

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SUMMARYActinobacteriaare Gram-positive bacteria with high G+C DNA content that constitute one of the largest bacterial phyla, and they are ubiquitously distributed in both aquatic and terrestrial ecosystems. ManyActinobacteriahave a mycelial lifestyle and undergo complex morphological differentiation. They also have an extensive secondary metabolism and produce about two-thirds of all naturally derived antibiotics in current clinical use, as well as many anticancer, anthelmintic, and antifungal compounds. Consequently, these bacteria are of major importance for biotechnology, medicine, and agriculture.Actinobacteriaplay diverse roles in their associations with various higher organisms, since their members have adopted different lifestyles, and the phylum includes pathogens (notably, species ofCorynebacterium,Mycobacterium,Nocardia,Propionibacterium, andTropheryma), soil inhabitants (e.g.,MicromonosporaandStreptomycesspecies), plant commensals (e.g.,Frankiaspp.), and gastrointestinal commensals (Bifidobacteriumspp.).Actinobacteriaalso play an important role as symbionts and as pathogens in plant-associated microbial communities. This review presents an update on the biology of this important bacterial phylum.

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Section: Correlation Between Growth and Antibiotic Productionmentioning

confidence: 99%

Taxonomy, Physiology, and Natural Products of Actinobacteria

Barka

Vatsa

Sanchez

et al. 2016

Microbiol Mol Biol Rev

1,530

1,048

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“…This consensus sequence is entirely consistent with the results of a recent microarray study that identified a group of 18 genes, including sigU and 6 of the regulon members proposed here, as having similar expression profiles during growth of M600 S. coelicolor on a maltose-based solid medium (see reference 25, additional data file 6, QT cluster 11). This group identified a common DNA sequence upstream of a subset of these similarly expressed genes that is the same as the U -dependent promoter consensus sequence reported here, with the exception that more variability was allowed at the fifth position of the Ϫ35 element (25). It will be important to characterize the full range of DNA sequences recognized by U to fully define this regulon.…”

Section: Discussionmentioning

confidence: 99%

Secreted-Protein Response to σ^UActivity inStreptomyces coelicolor

et al. 2008

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The filamentous bacterium Streptomyces coelicolor forms an aerial mycelium as a prerequisite to sporulation, which occurs in the aerial hyphae. Uncontrolled activity of the extracytoplasmic function sigma factor U blocks the process of aerial mycelium formation in this organism. Using a green fluorescent protein transcriptional reporter, we have demonstrated that sigU transcription is autoregulated. We have defined a U -dependent promoter sequence and used this to identify 22 likely U regulon members in the S. coelicolor genome. Since many of these genes encode probable secreted proteins, we characterized the extracellular proteome of a mutant with high U activity caused by disruption of rsuA, the presumed cognate anti-sigma factor of U . This mutant secreted a much greater quantity and diversity of proteins than the wild-type strain. Peptide mass fingerprinting was used to identify 79 proteins from the rsuA mutant culture supernatant. The most abundant species, SCO2217, SCO0930, and SCO2207, corresponded to secreted proteins or lipoproteins of unknown functions whose genes are in the proposed U regulon. Several unique proteases were also detected in the extracellular proteome of the mutant, and the levels of the protease inhibitor SCO0762 were much reduced compared to those of the wild type. Consequently, extracellular protease activity was elevated about fourfold in the rsuA mutant. The functions of the proteins secreted as a result of U activity may be important for combating cell envelope stress and modulating morphological differentiation in S. coelicolor.The Streptomyces species of gram-positive soil bacteria exhibit a complex life cycle that culminates in the production of unigenomic spores by sporulation of multigenomic, filamentous hyphae (8,56). While vegetative growth is characterized by the extension and branching of hyphae over and into the substratum, sporulation requires the construction of a distinct aerial mycelium composed of aerial hyphae that project above the colony surface. A number of mutants of the model organism Streptomyces coelicolor that fail to form an aerial mycelium have been described; these so-called bald (bld) mutants often have defects in antibiotic production, which is another hallmark of this genus. Many of the corresponding bld genes have been identified, and most are predicted to encode regulatory proteins (reviewed in reference 9).A growing body of evidence suggests that pathways mediating environmental stress responses and morphological development are linked in S. coelicolor (9,19,31,35,36,62). The functions of alternative sigma factors appear to play an important role in connecting these processes. The S. coelicolor genome encodes 65 sigma factors (4

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“…Nutrients, including N-acetylglucosamine, and autoregulatory factors, such as ␥-butyrolactones, can regulate antibiotic production through DasR-and AdpA-mediated signaling pathways, respectively (14,15). Other global regulatory systems, including the two-component system (TCS), ppGpp, alternative sigma factors, etc., all play essential roles in antibiotic production (16)(17)(18)(19). Most of the signaling pathways cross talk and converge on the promoters of synthesis gene clusters or the pathway-specific regulator genes for proper production of antibiotics (20).…”

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Positive Feedback Regulation of stgR Expression for Secondary Metabolism in Streptomyces coelicolor

et al. 2013

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LysR-type transcriptional regulators (LTTRs) compose a large family and are responsible for various physiological functions in bacteria, while little is understood about their regulatory mechanism on secondary metabolism in Streptomyces. Here we reported that StgR, a typical LTTR in Streptomyces coelicolor, was a negative regulator of undecylprodigiosin (Red) and ␥-actinorhodin (Act) production in the early developmental phase of secondary metabolism by suppressing the expression of two pathway-specific regulator genes, redD and actII-orf4, respectively. Meanwhile, stgR expression was downregulated during secondary metabolism to remove its repressive effects on antibiotic production. Moreover, stgR expression was positively autoregulated by direct binding of StgR to its own promoter (stgRp), and the binding site adjacent to translation start codon was determined by a DNase I footprinting assay. Furthermore, the StgR-stgRp interaction could be destroyed by the antibiotic ␥-actinorhodin produced from S. coelicolor. Thus, our results suggested a positive feedback regulatory mechanism of stgR expression and antibiotic production for the rapid and irreversible development of secondary metabolism in Streptomyces. LysR-type transcriptional regulators (LTTRs), first named after LysR, a transcriptional activator of lysA in Escherichia coli (1), have expanded considerably to the largest family after 3 decades and spread ubiquitously in bacteria. They have been structurally well characterized to have a conserved helix-turn-helix (HTH) motif at the N terminus for DNA binding and a regulatory domain for substrate or inducer binding at the C terminus (2). Consistent with their wide distributions and great quantities, they have diverse and conserved regulatory functions in bacteria for primary metabolism (3, 4), secondary metabolism (5, 6), stress responses (7), cell division (8), virulence (9, 10), protection (11), etc. Typically, most LTTRs function as the global transcriptional regulators by directly binding to the promoters of their regulons. Upon signaling, the assimilated extracellular ligands or produced intracellular metabolites can act as substrates or inducers to interact with the C-terminal domain to cause conformation changes to influence the DNA-binding affinity of LTTRs (2, 12).Species of Streptomyces, the soil-dwelling Gram-positive bacteria, are well-known for their complex morphogenesis and secondary metabolism. Among their abundant secondary metabolites, antibiotics are produced with patent clinical or commercial applications (13). The onset of secondary metabolism is triggered by environmental stimuli, and subsequent intracellular signaling pathways are equally required for felicitous development of secondary metabolism (14). Nutrients, including N-acetylglucosamine, and autoregulatory factors, such as ␥-butyrolactones, can regulate antibiotic production through DasR-and AdpA-mediated signaling pathways, respectively (14, 15). Other global regulatory systems, including the two-component system (TCS), ppGpp, ...

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The global role of ppGpp synthesis in morphological differentiation and antibiotic production in Streptomyces coelicolor A3(2)

Cited by 132 publications

References 69 publications

Taxonomy, Physiology, and Natural Products of Actinobacteria

Taxonomy, Physiology, and Natural Products of Actinobacteria

Secreted-Protein Response to σ^UActivity inStreptomyces coelicolor

Positive Feedback Regulation of stgR Expression for Secondary Metabolism in Streptomyces coelicolor

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The global role of ppGpp synthesis in morphological differentiation and antibiotic production in Streptomyces coelicolor A3(2)

Cited by 132 publications

References 69 publications

Taxonomy, Physiology, and Natural Products of Actinobacteria

Taxonomy, Physiology, and Natural Products of Actinobacteria

Secreted-Protein Response to σUActivity inStreptomyces coelicolor

Positive Feedback Regulation of stgR Expression for Secondary Metabolism in Streptomyces coelicolor

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Secreted-Protein Response to σ^UActivity inStreptomyces coelicolor