Antibiotic production by actinomycetes: the Janus faces of regulation

Cundliffe, Eric

doi:10.1007/s10295-006-0083-6

Cited by 32 publications

(22 citation statements)

References 35 publications

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“…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%

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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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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“…25 A profound examination of antibiotic biosynthetic gene clusters requires the use of a wide variety of recombinant DNA techniques, including the genetic modification of relevant strains that produce them, a requisite that can often not be fulfilled. A reasonable approach to overcome this problem is to express the antibiotic gene clusters in a heterologous host amenable to gene manipulation, like Streptomyces lividans or S. coelicolor.…”

Section: Resultsmentioning

confidence: 99%

Characterization of the biosynthetic gene cluster (ata) for the A201A aminonucleoside antibiotic from Saccharothrix mutabilis subsp. capreolus

et al. 2016

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Antibiotic A201A produced by Saccharothrix mutabilis subsp. capreolus NRRL3817 contains an aminonucleoside (N 6 , N 6 -dimethyl-3ʹ-amino-3ʹ-deoxyadenosyl), a polyketide (α-methyl-p-coumaric acid) and a disaccharide moiety. The heterologous expression in Streptomyces lividans and Streptomyces coelicolor of a S. mutabilis genomic region of~34 kb results in the production of A201A, which was identified by microbiological, biochemical and physicochemical approaches, and indicating that this region may contain the entire A201A biosynthetic gene cluster (ata). The analysis of the nucleotide sequence of the fragment reveals the presence of 32 putative open reading frames (ORF), 28 of which according to boundary gene inactivation experiments are likely to be sufficient for A201A biosynthesis. Most of these ORFs could be assigned to the biosynthesis of the antibiotic three structural moieties. Indeed, five ORFs had been previously implicated in the biosynthesis of the aminonucleoside moiety, at least nine were related to the biosynthesis of the polyketide (ata-PKS1-ataPKS4, ata18, ata19, ata2, ata4 and ata7) and six were associated with the synthesis of the disaccharide (ata12, ata13, ata16, ata17, ata5 and ata10) moieties. In addition to AtaP5, three putative methyltransferase genes are also found in the ata cluster (Ata6, Ata8 and Ata11), and no regulatory genes were found.

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“…The first three (RslR1, RslR2, and RslR3) are SARP (Streptomyces Antibiotic Regulatory Protein) family regulators. Because most reported antibiotic biosynthesis clusters from Streptomyces harbor only one SARP-encoding gene, [40] the occurrence of 3 SARP-type regulators in the rishirilide gene cluster is quite unusual. This might help to explain the nonreproduciblility of rishirilide A (4) production in S. bottropensis.…”

Section: Analysis Of the Rishirilide Biosynthetic Gene Clustermentioning

confidence: 98%

Cloning and Heterologous Expression of Three Type II PKS Gene Clusters from Streptomyces bottropensis

Yan¹,

Probst²,

Linnenbrink³

et al. 2011

ChemBioChem

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Mensacarcin is a potent cytotoxic agent isolated from Streptomyces bottropensis. It possesses a high content of oxygen atoms and two epoxide groups, and shows cytostatic and cytotoxic activity comparable to that of doxorubicin, a widely used drug for antitumor therapy. Another natural compound, rishirilide A, was also isolated from the fermentation broth of S. bottropensis. Screening a cosmid library of S. bottropensis with minimal PKS-gene-specific primers revealed the presence of three different type II polyketide synthase (PKS) gene clusters in this strain: the msn cluster (mensacarcin biosynthesis), the rsl cluster (rishirilide biosynthesis), and the mec cluster (putative spore pigment biosynthesis). Interestingly, luciferase-like oxygenases, which are very rare in Streptomyces species, are enriched in both the msn cluster and the rsl cluster. Three cosmids, cos2 (containing the major part of the msn cluster), cos3 (harboring the mec cluster), and cos4 (spanning probably the whole rsl cluster) were introduced into the general heterologous host Streptomyces albus by intergeneric conjugation. Expression of cos2 and cos4 in S. albus led to the production of didesmethylmensacarcin (DDMM, a precursor of mensacarcin) and the production of rishirilide A and B (a precursor of rishirilide A), respectively. However, no product was detected from the expression of cos3. In addition, based on the results of isotope-feeding experiments in S. bottropensis, a putative biosynthesis pathway for mensacarcin is proposed.

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Antibiotic production by actinomycetes: the Janus faces of regulation

Cited by 32 publications

References 35 publications

A Complex Signaling Cascade Governs Pristinamycin Biosynthesis in Streptomyces pristinaespiralis

A Complex Signaling Cascade Governs Pristinamycin Biosynthesis in Streptomyces pristinaespiralis

Characterization of the biosynthetic gene cluster (ata) for the A201A aminonucleoside antibiotic from Saccharothrix mutabilis subsp. capreolus

Cloning and Heterologous Expression of Three Type II PKS Gene Clusters from Streptomyces bottropensis

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