Streptomyces ghanaensis pleiotropic regulatory gene wblA gh influences morphogenesis and moenomycin production

Rabyk, Mariia; Ostash, Bohdan; Rebets, Yurij; Walker, Suzanne; Fedorenko, Victor

doi:10.1007/s10529-011-0728-z

Cited by 35 publications

(29 citation statements)

References 14 publications

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“…Previous reports have shown that WblA and its orthologues act as negative regulators for antibiotic biosynthesis in various Streptomyces species and that wblA deletion mutants lead to overproduction of the corresponding antibiotics (21)(22)(23)(24). In order to identify the function of wblA ch in natamycin biosynthesis in S. chattanoogensis L10, a wblA ch deletion mutant was constructed via homologous recombination, as described Materials and Methods.…”

Section: Resultsmentioning

confidence: 99%

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WblA_ch, a Pivotal Activator of Natamycin Biosynthesis and Morphological Differentiation in Streptomyces chattanoogensis L10, Is Positively Regulated by AdpA_ch

Liu

et al. 2014

Appl Environ Microbiol

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bDetailed mechanisms of WhiB-like (Wbl) proteins involved in antibiotic biosynthesis and morphological differentiation are poorly understood. Here, we characterize the role of WblA ch , a Streptomyces chattanoogensis L10 protein belonging to this superfamily. Based on DNA microarray data and verified by real-time quantitative PCR (qRT-PCR), the expression of wblA ch was shown to be positively regulated by AdpA ch . Gel retardation assays and DNase I footprinting experiments showed that AdpA ch has specific DNA-binding activity for the promoter region of wblA ch . Gene disruption and genetic complementation revealed that WblA ch acts in a positive manner to regulate natamycin production. When wblA ch was overexpressed in the wild-type strain, the natamycin yield was increased by ϳ30%. This provides a strategy to generate improved strains for natamycin production. Moreover, transcriptional analysis showed that the expression levels of whi genes (including whiA, whiB, whiH, and whiI) were severely depressed in the ⌬wblA ch mutant, suggesting that WblA ch plays a part in morphological differentiation by influencing the expression of the whi genes.

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Section: Resultsmentioning

confidence: 99%

“…WblA and its orthologues have been described as crucial antibiotic downregulators for the biosynthesis of various antibiotics such as actinorhodin (21), doxorubicin (22), tautomycetin (23), and moenomycin (24). Moreover, it was discovered that wblA is negatively regulated by the pleiotropic regulator AdpA in S. coelicolor (25).…”

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confidence: 99%

WblA_ch, a Pivotal Activator of Natamycin Biosynthesis and Morphological Differentiation in Streptomyces chattanoogensis L10, Is Positively Regulated by AdpA_ch

Liu

et al. 2014

Appl Environ Microbiol

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“…In fact, orthologs of SCO3579 (wblA) have been used for strain improvement for Streptomyces ghanaensis and Streptomyces peucetius (70,71). The additive effects of different modulators of antibiotic production have been applied in engineering optimized hosts for heterologous expression of antibiotic pathway gene sets (72).…”

Section: Discussionmentioning

confidence: 99%

Large-Scale Transposition Mutagenesis of Streptomyces coelicolor Identifies Hundreds of Genes Influencing Antibiotic Biosynthesis

Wang

Chater

et al. 2017

Appl Environ Microbiol

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Gram-positive Streptomyces bacteria produce thousands of bioactive secondary metabolites, including antibiotics. To systematically investigate genes affecting secondary metabolism, we developed a hyperactive transposase-based Tn5 transposition system and employed it to mutagenize the model species Streptomyces coelicolor, leading to the identification of 51,443 transposition insertions. These insertions were distributed randomly along the chromosome except for some preferred regions associated with relatively low GC content in the chromosomal core. The base composition of the insertion site and its flanking sequences compiled from the 51,443 insertions implied a 19-bp expanded target site surrounding the insertion site, with a slight nucleic acid base preference in some positions, suggesting a relative randomness of Tn5 transposition targeting in the high-GC Streptomyces genome. From the mutagenesis library, 724 mutants involving 365 genes had altered levels of production of the tripyrrole antibiotic undecylprodigiosin (RED), including 17 genes in the RED biosynthetic gene cluster. Genetic complementation revealed that most of the insertions (more than two-thirds) were responsible for the changed antibiotic production. Genes associated with branched-chain amino acid biosynthesis, DNA metabolism, and protein modification affected RED production, and genes involved in signaling, stress, and transcriptional regulation were overrepresented. Some insertions caused dramatic changes in RED production, identifying future targets for strain improvement.IMPORTANCE High-GC Gram-positive streptomycetes and related actinomycetes have provided more than 100 clinical drugs used as antibiotics, immunosuppressants, and antitumor drugs. Their genomes harbor biosynthetic genes for many more unknown compounds with potential as future drugs. Here we developed a useful genomewide mutagenesis tool based on the transposon Tn5 for the study of secondary metabolism and its regulation. Using Streptomyces coelicolor as a model strain, we found that chromosomal insertion was relatively random, except at some hot spots, though there was evidence of a slightly preferred 19-bp target site. We then used prodiginine production as a model to systematically survey genes affecting antibiotic biosynthesis, providing a global view of antibiotic regulation. The analysis revealed 348 genes that modulate antibiotic production, among which more than half act to reduce production. These might be valuable targets in future investigations of regulatory mechanisms, for strain improvement, and for the activation of silent biosynthetic gene clusters.KEYWORDS genome-wide, transposition mutagenesis, Streptomyces coelicolor, antibiotic biosynthesis, prodiginine

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“…Disruption of wblA dramatically increased antibiotic production in S. coelicolor (195), Streptomyces peucetius (196), and Streptomyces sp. strain C4412 (197), prevented nearly all aerial hyphae from sporulating in S. coelicolor (195) and Streptomyces ghanaensis (198), affected the expression of hundreds of genes in S. coelicolor (195), and slightly increased S. coelicolor oxidative stress responses (199). On the other hand, a high copy number of wblA depressed the production of ACT, RED, and CDA in S. coelicolor (and of doxorubicin in S. peucetius) (200).…”

Section: How Does Bldd Regulate Development and Antibiotic Production?mentioning

confidence: 99%

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

Liu

Chater

Chandra

et al. 2013

Microbiol Mol Biol Rev

610

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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Streptomyces ghanaensis pleiotropic regulatory gene wblA gh influences morphogenesis and moenomycin production

Cited by 35 publications

References 14 publications

WblA_ch, a Pivotal Activator of Natamycin Biosynthesis and Morphological Differentiation in Streptomyces chattanoogensis L10, Is Positively Regulated by AdpA_ch

WblA_ch, a Pivotal Activator of Natamycin Biosynthesis and Morphological Differentiation in Streptomyces chattanoogensis L10, Is Positively Regulated by AdpA_ch

Large-Scale Transposition Mutagenesis of Streptomyces coelicolor Identifies Hundreds of Genes Influencing Antibiotic Biosynthesis

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

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Streptomyces ghanaensis pleiotropic regulatory gene wblA gh influences morphogenesis and moenomycin production

Cited by 35 publications

References 14 publications

WblAch, a Pivotal Activator of Natamycin Biosynthesis and Morphological Differentiation in Streptomyces chattanoogensis L10, Is Positively Regulated by AdpAch

WblAch, a Pivotal Activator of Natamycin Biosynthesis and Morphological Differentiation in Streptomyces chattanoogensis L10, Is Positively Regulated by AdpAch

Large-Scale Transposition Mutagenesis of Streptomyces coelicolor Identifies Hundreds of Genes Influencing Antibiotic Biosynthesis

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

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WblA_ch, a Pivotal Activator of Natamycin Biosynthesis and Morphological Differentiation in Streptomyces chattanoogensis L10, Is Positively Regulated by AdpA_ch

WblA_ch, a Pivotal Activator of Natamycin Biosynthesis and Morphological Differentiation in Streptomyces chattanoogensis L10, Is Positively Regulated by AdpA_ch