Hierarchical control of virginiamycin production in Streptomyces virginiae by three pathway-specific regulators: VmsS, VmsT and VmsR

Pulsawat, Nattika; Kitani, Shigeru; Fukushima, Eriko; Nihira, Takuya

doi:10.1099/mic.0.022467-0

Cited by 27 publications

(29 citation statements)

References 24 publications

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“…S1A in the supplemental material). However, a closer look at the abundance of different regulator types and their function, which has been partially shown for virginiamycin regulation (15,16,56,57,58) but only deduced for GV/VG regulation (55), suggests that there exist different regulatory networks in all streptogramin producers (see Fig. S1B in the supplemental material): e.g., the virginiamycin cascade has no equivalent for PapR1 and PapR5 in abundance and function.…”

Section: Putative Interaction Partners Of Response Regulator Papr6mentioning

confidence: 99%

“…The best-understood model for a targeted coordination of antibiotic biosynthesis is the A-factor regulatory cascade of Streptomyces griseus, which controls streptomycin biosynthesis (14). Further examples have been reported, e.g., for the regulation of the pristinamycin-related antibiotic virginiamycin of Streptomyces virginiae (15,16), tylosin production in Streptomyces fradiae (17), lankacidin/lankamycin biosynthesis in Streptomyces rochei (18), or auricin biosynthesis in Streptomyces aureofaciens (19).…”

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confidence: 99%

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A Complex Signaling Cascade Governs Pristinamycin Biosynthesis in Streptomyces pristinaespiralis

Mast

Guezguez

Handel

et al. 2015

Appl Environ Microbiol

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Pristinamycin production in Streptomyces pristinaespiralis Pr11 is tightly regulated by an interplay between different repressors and activators. A ␥-butyrolactone receptor gene (spbR), two TetR repressor genes (papR3 and papR5), three SARP (Streptomyces antibiotic regulatory protein) genes (papR1, papR2, and papR4), and a response regulator gene (papR6) are carried on the large 210-kb pristinamycin biosynthetic gene region of Streptomyces pristinaespiralis Pr11. A detailed investigation of all pristinamycin regulators revealed insight into a complex signaling cascade, which is responsible for the fine-tuned regulation of pristinamycin production in S. pristinaespiralis. Streptomycetes are filamentous, Gram-positive soil bacteria that are well known for their ability to produce varieties of bioactive secondary metabolites, including more than 70% of the commercially important antibiotics (1). The production of antibiotics is controlled by a vast array of physiological and nutritional conditions, communicated by extracellular and intracellular signaling molecules (2). The beginning of antibiotic biosynthesis is often coordinated with processes of morphological differentiation. The characteristic Streptomyces life cycle involves the formation of a feeding substrate mycelium and subsequent development of aerial hyphae, which finally septate into spores (3). Generally, antibiotic production begins as the culture enters stationary growth in liquid culture and coincidences with the onset of morphological differentiation in agar-grown cultures (reviewed in reference 4). In many Streptomyces strains, antibiotic production is regulated by low-molecular-weight compounds, called ␥-butyrolactone autoregulators (GBLs) (5, 6). GBLs are small diffusible signaling molecules that are synthesized and gradually accumulated in a growth-dependent manner, at or near the middle of the exponential phase of Streptomyces growth, when they trigger the onset of antibiotic biosynthesis and/or morphological differentiation at nanomolar concentrations (7). Often, the GBL signal is transmitted via a hierarchical signaling cascade including pleiotropic and pathway-specific regulators, which all together control the antibiotic production: when the GBL concentration reaches a critical level, the signal is transmitted into the cells by binding to specific cytoplasmic receptor proteins, the GBL receptors (7). GBL receptors belong to the TetR family of transcriptional regulators (8). In the absence of the corresponding ligand, the GBL receptor binds to conserved AT-rich, partially palindromic sequences (9), the so-called "ARE" sequences (autoregulatory element) (10), within the promoter regions of its target genes and thereby represses the transcription of these genes. By binding of the GBLs to their receptors, the latter undergo a conformational change and dissociate from the target DNA, allowing expression of the derepressed genes (11). Predominantly, targets of GBL receptors are transcriptional regulatory genes, such as TetR and SARP (Streptomyce...

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Section: Putative Interaction Partners Of Response Regulator Papr6mentioning

confidence: 99%

mentioning

confidence: 99%

A Complex Signaling Cascade Governs Pristinamycin Biosynthesis in Streptomyces pristinaespiralis

Mast

Guezguez

Handel

et al. 2015

Appl Environ Microbiol

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“…However, either papR6 inactivation or overexpression had almost no effect on PI (PIa) biosynthesis. These results clearly demonstrated that PapR6 functions as a pathway-specific activator of PII production in S. pristinaespiralis, resembling the function of its homolog VmsT from S. virginiae (22).…”

Section: Resultsmentioning

confidence: 56%

“…Hence, the role of VmsT in VM biosynthesis is likely indirect. It was suggested that VmsT may regulate the expression of another, unidentified gene(s) outside the VM biosynthetic gene cluster and then activate VM biosynthesis (22). Here we revealed that the role of PapR6 in PII biosynthesis is possibly exerted via directly controlling the transcription of the snaFE1E2GHIJK gene cluster.…”

Section: Discussionmentioning

confidence: 64%

“…In this study, papR6, which encodes a putative atypical response regulator (ARR), was characterized to function as a pathway-specific activator gene for PII biosynthesis in S. pristinaespiralis, which resembles the role of its homolog vmsT, a pathway-specific regulator gene for VM (an antibiotic similar to PII) biosynthesis in S. virginiae (22). However, unlike vmsT, whose disruption resulted in a loss of VM biosynthesis, inactivation of papR6 led to only about a 30 to 40% reduction in PII production.…”

Section: Discussionmentioning

confidence: 99%

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PapR6, a Putative Atypical Response Regulator, Functions as a Pathway-Specific Activator of Pristinamycin II Biosynthesis in Streptomyces pristinaespiralis

Dun¹,

Zhao²,

Zheng³

et al. 2014

J. Bacteriol.

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cThere are up to seven regulatory genes in the pristinamycin biosynthetic gene cluster of Streptomyces pristinaespiralis, which infers a complicated regulation mechanism for pristinamycin production. In this study, we revealed that PapR6, a putative atypical response regulator, acts as a pathway-specific activator of pristinamycin II (PII) biosynthesis. Deletion of the papR6 gene resulted in significantly reduced PII production, and its overexpression led to increased PII formation, compared to that of the parental strain HCCB 10218. However, either papR6 deletion or overexpression had very little effect on pristinamycin I (PI) biosynthesis. Electrophoretic mobility shift assays (EMSAs) demonstrated that PapR6 bound specifically to the upstream region of snaF, the first gene of the snaFE1E2GHIJK operon, which is likely responsible for providing the precursor isobutyryl-coenzyme A (isobutyryl-CoA) and the intermediate C 11 ␣␤-unsaturated thioester for PII biosynthesis. A signature PapR6-binding motif comprising two 4-nucleotide (nt) inverted repeat sequences (5=-GAGG-4 nt-CCTC-3=) was identified. Transcriptional analysis showed that inactivation of the papR6 gene led to markedly decreased expression of snaFE1E2GHIJK. Furthermore, we found that a mutant (snaFmu) with base substitutions in the identified PapR6-binding sequence in the genome exhibited the same phenotype as that of the ⌬papR6 strain. Therefore, it may be concluded that pathway-specific regulation of PapR6 in PII biosynthesis is possibly exerted via controlling the provision of isobutyryl-CoA as well as the intermediate C 11 ␣␤-unsaturated thioester. Streptomyces pristinaespiralis produces pristinamycin, which is a streptogramin-like antibiotic and a mixture of two structurally different components: pristinamycin I (PI), a branched cyclic hexadepsipeptide, and pristinamycin II (PII), a polyunsaturated cyclopeptide macrolactone (1). PI and PII are cosynthesized at a ratio of 30:70 and show strong synergistic activity. The combined application of both components yields an antibacterial activity up to 100 times higher than that of each single component (2). Pristinamycin is attracting more and more interest for its activity against many multiple-drug-resistant Gram-positive bacteria, such as methicillin-resistant staphylococci and vancomycin-resistant Enterococcus faecium (2).The gene cluster responsible for the biosynthesis of PI and PII has been well characterized for S. pristinaespiralis (3-9); all essential PI/PII biosynthetic genes are proposed to be included in a 210-kb "supercluster," in which the pristinamycin gene cluster is interspersed with a cryptic type II polyketide biosynthetic gene cluster (10). Interestingly, there are seven regulatory genes in the pristinamycin biosynthetic gene cluster, including papR1 to papR6 and spbR, which infers a complicated regulatory mechanism for pristinamycin production. It has long been suggested that manipulation of the regulatory network governing antibiotic biosynthesis in Streptomyces may represent an ef...

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Identification of the Biosynthetic Gene Cluster and Regulatory Cascade for the Synergistic Antibacterial Antibiotics Griseoviridin and Viridogrisein in Streptomyces griseoviridis

et al. 2012

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Griseoviridin (GV) and viridogrisein (VG, also referred to as etamycin), produced by Streptomyces griseoviridis, are two chemically unrelated compounds belonging to the streptogramin family. Both of these natural products demonstrate broad-spectrum antibacterial activity and constitute excellent candidates for future drug development. To elucidate the biosynthetic machinery associated with production of these two unique antibiotics, the gene cluster responsible for both GV and VG production was identified within the Streptomyces griseoviridis genome and characterized, and its function in GV and VG biosynthesis was confirmed by inactivation of 30 genes and complementation experiments. This sgv gene cluster is localized to a 105 kb DNA region that consists of 36 open reading frames (ORFs), including four nonribosomal peptide synthetases (NRPSs) for VG biosynthesis and a set of hybrid polyketide synthases (PKS)-NRPSs with a discrete acyltransferase (AT), SgvQ, to assemble the GV backbone. The enzyme encoding genes for VG versus GV biosynthesis are separated into distinct "halves" of the cluster. A series of four genes: sgvA, sgvB, sgvC, and sgvK, were found downstream of the PKS-NRPS; these likely code for construction of a γ-butyrolactone (GBL)-like molecule. GBLs and the corresponding GBL receptor systems are the highest ranked regulators that are able to coordinate the two streptomyces antibiotic regulatory protein (SARP) family positive regulators SgvR2 and SgvR3; both are key biosynthetic activators. Models of GV, VG, and GBL biosynthesis were proposed by using functional gene assignments, determined on the basis of bioinformatics analysis and further supported by in vivo gene inactivation experiments. Overall, this work provides new insights into the biosyntheses of the GV and VG streptogramins that are potentially applicable to a host of combinatorial biosynthetic scenarios.

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Hierarchical control of virginiamycin production in Streptomyces virginiae by three pathway-specific regulators: VmsS, VmsT and VmsR

Cited by 27 publications

References 24 publications

A Complex Signaling Cascade Governs Pristinamycin Biosynthesis in Streptomyces pristinaespiralis

A Complex Signaling Cascade Governs Pristinamycin Biosynthesis in Streptomyces pristinaespiralis

PapR6, a Putative Atypical Response Regulator, Functions as a Pathway-Specific Activator of Pristinamycin II Biosynthesis in Streptomyces pristinaespiralis

Identification of the Biosynthetic Gene Cluster and Regulatory Cascade for the Synergistic Antibacterial Antibiotics Griseoviridin and Viridogrisein in Streptomyces griseoviridis

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