On-PKS Baeyer–Villiger-Type O‑Atom Insertion Catalyzed by Luciferase-Like Monooxygenase OvmO during Olimycin Biosynthesis

A silent ansamycin biosynthetic gene cluster (ovm) was activated in Streptomyces olivaceus SCSIO T05 following mutagenesis and media optimization. A new shunt product, olimycin C (1a) was produced by the ovmO-inactivated mutant strain, along with a minor product, olimycin D (1b). The production of these linear olimycin counterparts suggest that luciferase-like monooxygenase (LLM) OvmO catalyzes an on-PKS Baeyer–Villiger-type oxidation during assembly of the olimycin A (2) linear polyketide backbone

Migrastatin and Dorrigocins Are Shunt Metabolites of Iso-Migrastatin

Fermentation of Streptomyces platensis NRRL18993 typically accumulated migrastation (1), dorrigocin A (2) and B (3), and 13-epi-dorrigocin A (5). Supplement of XAD-16 resin to the fermentation, in contrast, resulted in exclusive production of iso-migrastatin (4). In vitro studies showed that 1, 2, 3, and 5 are stable in aqueous solution but 4 undergoes rapid conversion into 1, 2, 3, and 5 under the same condition. These results revealed that 4 is the only bona fide natural product biosynthesized by S. platensis, and 1, 2, 3, and 5 are shunt metabolites of 4. This study also established the stereochemistry of 2−5 with the exception of C-11 for 3 and 4. A mechanism for H2O-mediated regio- and stereospecific rearrangement of 4 to 1, 2, 3, and 5 is proposed and supported by incorporation of 18O from H218O

Octyl substituted butenolides from marine-derived <i>Streptomyces koyangensis</i>

A new butenolide derivative (1) featuring octyl substitution at γ-position, together with four known analogues (2–5) were isolated from marine-derived Streptomyces koyangensis SCSIO 5802. The structure of 1 was elucidated by HR-MS and NMR spectroscopic data analyses. The absolute configuration of the stereo centre in lactone ring of 1 was determined by comparison of CD spectrum with those of known compounds. Compound 1 exhibited mild antiviral activity against herpes simplex virus with EC50 value of 25.4 µM.</p

Presentation_1_Genome Sequencing of Streptomyces atratus SCSIOZH16 and Activation Production of Nocardamine via Metabolic Engineering.pdf

The Actinomycetes are metabolically flexible microorganisms capable of producing a wide range of interesting compounds, including but by no means limited to, siderophores which have high affinity for ferric iron. In this study, we report the complete genome sequence of marine-derived Streptomyces atratus ZH16 and the activation of an embedded siderophore gene cluster via the application of metabolic engineering methods. The S. atratus ZH16 genome reveals that this strain has the potential to produce 26 categories of natural products (NPs) barring the ilamycins. Our activation studies revealed S. atratus SCSIO ZH16 to be a promising source of the production of nocardamine-type (desferrioxamine) compounds which are important in treating acute iron intoxication and performing ecological remediation. We conclude that metabolic engineering provides a highly effective strategy by which to discover drug-like compounds and new NPs in the genomic era.</p

Metabolic Blockade-Based Genome Mining Reveals Lipochain-Linked Dihydro-β-alanine Synthetases Involved in Autucedine Biosynthesis

Continuously mining the Streptomyces olivaceus SCSIO T05 genome leads to the identification of new lipopeptides (autucedines A–C), constituting members of the 10th skeleton isolated from this strain. The corresponding biosynthetic gene cluster (aut) was verified by heterogeneous expression, and another two analogues (autucedines D and E) were isolated from the heterogeneous expression strain. Gene inactivation experiments revealed that construction of the unique “lipochain-linked dihydro-β-alanine” unit takes place prior to the NRPS assembly line

Discovery, Structure Correction, and Biosynthesis of Actinopyrones, Cytotoxic Polyketides from the Deep-Sea Hydrothermal-Vent-Derived <i>Streptomyces</i> sp. SCSIO ZS0520

Three new actinopyrone derivatives, actinopyrones E–G (1, 3, and 4), together with three known analogues, PM050463 (2), actinopyrone D (5), and PM050511 (6), were isolated from Streptomyces sp. SCSIO ZS0520 derived from a deep-sea hydrothermal vent. Their structures, complete with absolute configurations, were elucidated using extensive spectroscopic analyses combined with Mosher’s method, ECD calculations, and bioinformatics analyses. These findings corrected the absolute configurations of previously reported actinopyrone analogues 2, 5, and 6 at C-3, C-9, and C-10. Notably, compound 6 displayed notable cytotoxicity against six human cell lines with IC50 values of 0.26–2.22 μM. A likely biosynthetic pathway and annotations of protein function are proposed on the basis of bioinformatics analyses. Genes coding for methyltransferase and glycosyltransferase tailoring chemistries needed to generate final structures were notably absent from the biosynthetic gene cluster. Taken together, these results enable further bioengineering of the actinopyrones and related congeners as potential antitumor agents

Iso-Migrastatin Congeners from <i>Streptomyces </i><i>p</i><i>latensis</i> and Generation of a Glutarimide Polyketide Library Featuring the Dorrigocin, Lactimidomycin, Migrastatin, and NK30424 Scaffolds

Iso-Migrastatin (10) has been shown to be the main natural product of Streptomyces platensis, which undergoes a facile, H2O-mediated rearrangement into dorrigocin A (2), 13-epi-dorrigocin A (11), dorrigocin B (3), and migrastatin (1). Eight new congeners (12−19) of 10 were characterized. They can undergo the same H2O-mediated rearrangement into the corresponding 1, 2, 3, and 11 analogues (20−43) or 1,4-Michael addition with cysteine to afford the corresponding analogues (44−51) of NK30424 A and B (5, 6). This study generated a 47-member library of glutarimide polyketides, setting the stage to investigate the SAR for this family of natural products. These results also established the absolute stereochemistry of 5 and 6 and shed new light into the post-polyketide synthase steps for 10 biosynthesis

A new diketopiperazine derivative from a deep sea-derived <i>Streptomyces</i> sp. SCSIO 04496

<div><p>A new diketopiperazine (DKP) derivative, (6<i>R</i>,3<i>Z</i>)-3-benzylidene-6-isobutyl-1-methyl piperazine-2,5-dione (<b>1</b>), as well as five known DKPs <b>2</b>–<b>6</b> was isolated from a deep sea-derived <i>Streptomyces</i> sp. SCSIO 04496. The structure of <b>1</b> was elucidated using a combination of 1D and 2D NMR, HR-ESI-MS and chiral-phase HPLC techniques. Compounds <b>1</b>–<b>6</b> did not show cytotoxic activity at a concentration of 100 μM in bioactivity assay.</p></div

Cyclic Heptapeptides, Cordyheptapeptides C–E, from the Marine-Derived Fungus <i>Acremonium persicinum</i> SCSIO 115 and Their Cytotoxic Activities

Three new cycloheptapeptides, cordyheptapeptides C–E (1–3), were isolated from the fermentation extract of the marine-derived fungus Acremonium persicinum SCSIO 115. Their planar structures were elucidated on the basis of extensive MS, as well as 1D and 2D (COSY, HMQC, and HMBC) NMR spectroscopic data analyses. The absolute configurations of the amino acid residues were determined by single-crystal X-ray diffraction, Marfey’s method, and chiral-phase HPLC analysis. Compounds 1 and 3 displayed cytotoxicity against SF-268, MCF-7, and NCI-H460 tumor cell lines with IC50 values ranging from 2.5 to 12.1 μM

Antimicrobial tunicamycin derivatives from the deep sea-derived <i>Streptomyces xinghaiensis</i> SCSIO S15077

Tunicamycin E (1), featuring a methyl substitution at C-10′, was isolated from marine-derived Streptomyces xinghaiensis SCSIO S15077 originated from the South China Sea sediment together with six known compounds, tunicamycin B (2), tunicamycin X (3), tunicamycin A (4), streptovirudin D2 (5), tunicamycin C (6), and tunicamycin C3 (7). The structure of compound 1 was elucidated by detailed spectroscopic data analyses. All the compounds exhibited strong to moderate antibacterial activity against Gram-positive bacteria Bacillus thuringiensis BT01 and B. thuringiensis W102 with MIC values ranging from 0.008 to 2 μg/mL. Moreover, compounds 1–7 exhibited moderate antifungal activity against Candida albicans ATCC 96901 and C. albicans CMCC (F) 98001 with MIC values ranging from 2 to 32 μg/mL. This is the first report that tunicamycins exhibit antimicrobial activities against B. thuringiensis, C. albicans CMCC (F) 98001 and a fluconazole resistant strain C. albicans ATCC 96901.</p