Novel antibiotics, furaquinocins C, D, E, F, G and H.

Ishibashi, Masami; Funayama, Shinji; Anraku, Yumi; Komiyama, Kanki; Ōmura, Satoshi

doi:10.7164/antibiotics.44.390

Cited by 60 publications

(35 citation statements)

References 7 publications

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“…A major peak and a minor peak that were specifically detected in the culture broth of S. lividans TK23 harboring pWHM-Fura2 are indicated by the arrow and the asterisk, respectively. The structure corresponding to the former peak (FQ D) was determined by NMR and mass spectral analyses and is shown together with that of FQ A. purified, and its structure was determined to be that of FQ D (17). Compared with FQ D, FQ A has one additional hydroxyl group at the isoprenoid moiety (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Biosynthesis of a Natural Polyketide-Isoprenoid Hybrid Compound, Furaquinocin A: Identification and Heterologous Expression of the Gene Cluster

et al. 2006

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Furaquinocin (FQ) A, produced by Streptomyces sp. strain KO-3988, is a natural polyketide-isoprenoid hybrid compound that exhibits a potent antitumor activity. As a first step toward understanding the biosynthetic machinery of this unique and pharmaceutically useful compound, we have cloned an FQ A biosynthetic gene cluster by taking advantage of the fact that an isoprenoid biosynthetic gene cluster generally exists in flanking regions of the mevalonate (MV) pathway gene cluster in actinomycetes. Interestingly, Streptomyces sp. strain KO-3988 was the first example of a microorganism equipped with two distinct mevalonate pathway gene clusters. We were able to localize a 25-kb DNA region that harbored FQ A biosynthetic genes (fur genes) in both the upstream and downstream regions of one of the MV pathway gene clusters (MV2) by using heterologous expression in Streptomyces lividans TK23. This was the first example of a gene cluster responsible for the biosynthesis of a polyketide-isoprenoid hybrid compound. We have also confirmed that four genes responsible for viguiepinol [3-hydroxypimara-9(11),15-diene] biosynthesis exist in the upstream region of the other MV pathway gene cluster (MV1), which had previously been cloned from strain KO-3988. This was the first example of prokaryotic enzymes with these biosynthetic functions. By phylogenetic analysis, these two MV pathway clusters were identified as probably being independently distributed in strain KO-3988 (orthologs), rather than one cluster being generated by the duplication of the other cluster (paralogs).

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Section: Discussionmentioning

confidence: 99%

“…Fermentation was carried out for 7 days at 30°C with agitation (200 rpm). The culture broth (20 liters), containing approximately 0.2 g/ml of FQ D, was collected and the compound was purified as described by Ishibashi et al (17). The purity of the metabolite was examined by reverse-phase HPLC.…”

Section: Chemicals [␣-mentioning

confidence: 99%

Biosynthesis of a Natural Polyketide-Isoprenoid Hybrid Compound, Furaquinocin A: Identification and Heterologous Expression of the Gene Cluster

et al. 2006

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“…Among FQs, FQ H displays the strongest cytocidal activity, with an IC 50 value of 0.08 and 0.22 mg ml À1 against B16 melanoma cells and HeLa S3 cells, respectively. 12 The difference in activity level between FQ H and the novel compounds reported here may have resulted from the structural modification at C-14. Future research should investigate whether 1 and 2 display bioactivity in other assay systems.…”

Section: Biological Activity Of 1 Andmentioning

confidence: 84%

“…KO-3988, 11 have cytocidal activities without antibacterial activity. So far, eight analogues of these polyketide isoprenoid hybrid compounds ( Figure 1) [11][12][13] and their gene cluster 14 have been identified. However, no new analogues have been described since the discovery of FQ two decades ago.…”

Section: Introductionmentioning

confidence: 99%

Furaquinocins I and J: novel polyketide isoprenoid hybrid compounds from Streptomyces reveromyceticus SN-593

et al. 2011

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Two novel furaquinocin (FQ) analogues, I (1) and J (2), were isolated from Streptomyces reveromyceticus SN-593 strain NRM2. Their structures were elucidated by MS and NMR analyses. Similar to the previously described FQ D (3), both 1 and 2 possessed a dihydrofuran ring fused to a polyketide naphthoquinone skeleton. The main difference between 1, 2 and 3 was the type of residue attached to C-13; these were a carboxyl, a carboxamide and a methyl residue, respectively. INTRODUCTIONThe majority of bioactive compounds used as drugs and bioprobes originally derive from the secondary metabolites of microorganisms. Genome sequence analyses have shown that the number of bioactive compounds isolated from Streptomyces spp. is much lower than the number of gene clusters harbored by each species. [1][2][3] This indicates that the majority of gene clusters are either not expressed, or are only minimally expressed, under standard laboratory conditions. To discover novel natural products that are normally expressed at a very low level, we have been performing a systematic isolation of secondary metabolites. As a result, we isolated verticilactam 4 from Streptomyces spiroverticillatus JC-8444, a tautomycin producer, 5 and 6-dimethylallylindole-3-carbaldehyde 6 from S. reveromyceticus SN-593, a reveromycin producer. 7 In addition, from S. reveromyceticus SN-593, we detected metabolites showing UV spectra similar to furaquinocin (FQ), but different mass from the reported FQs. Consistent with the finding, we could annotate an FQ biosynthetic gene cluster from the genome draft sequence. However, with the quantity produced by wild type strain, it was not possible to isolate and determine the structure. So, in order to improve the production of novel FQ derivatives, we performed the expression of pathway-specific regulatory genes associated with the FQ biosynthetic gene cluster. Activation of pathwayspecific positive regulatory gene is commonly used for augmentation of secondary metabolites in Streptomyces. [8][9][10] FQs, originally isolated from the culture broth of Streptomyces sp. 11 have cytocidal activities without antibacterial activity. So far, eight analogues of these polyketide isoprenoid hybrid compounds (Figure 1) [11][12][13] and their gene cluster 14 have been identified.

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“…The structure of 1 is related to those of the furaquinocins, 9-13 in particular furaquinocin D, 11,12 isolated as the secondary metabolite of Streptomyces. As furaquinocins show cytotoxicity against cancer cells, we evaluated the cytotoxic activity of 1 against human cervical carcinoma HeLa cells by using a (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt (WST-8) colorimetric assay (Cell Counting Kit; Dojindo, Kumamoto, Japan) for 72 h. The results showed that 1 exhibited a weak cytotoxicity, with an IC 50 value of 44.4 mM.…”

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confidence: 99%

A new furaquinocin derivative, JBIR-136, from Streptomyces sp. 4963H2

et al. 2012

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Natural products are considered to be good sources for the screening of lead compounds of clinical drugs. We performed a large number of drug screenings by using a variety of assay systems with crude extracts of microbial cultures as a traditional natural product library. In some assay systems, our crude extract library could not work effectively. With this in mind, we started to construct a purified natural compound library possessing various skeletons from cultures of microorganisms. As actinomycetes are known to produce pharmaceutically useful compounds, 1,2 we focused mainly on secondary metabolites from cultures of actinomycetes. To achieve this, we established a high-throughput system for the detection of secondary metabolites from the cultures of actinomycetes with the retentiontime and HR-MS data of known compounds by using a UPLC-TOF-MS system (Waters, Milford, MA, USA). 3 We analyzed the secondary metabolites, including potential novel compounds, present in the cultures of the strains isolated from a variety of resources by this system. 3 In the course of our chemical screening program, a new furaquinocin derivative named JBIR-136 (1, Figure 1a), together with the known compound kujimycin A, 4 was isolated from a culture broth of Streptomyces sp. 4963H2. This paper describes the fermentation, isolation, structural elucidation and, in brief, the biological activity of 1.Streptomyces sp. 4963H2 was isolated from a soil sample collected in Kimitsu, Chiba Prefecture, Japan. The strain was cultivated in 50-ml test tubes, each containing 15 ml of a seed medium consisting of 1.0% starch (Kosokagaku, Tokyo, Japan), 1.0% polypeptone (Nihon Pharmaceutical, Tokyo, Japan), 1.0% molasses (Dai-Nippon Meiji Sugar, Tokyo, Japan) and 1.0% meat extract (Extract Ehlrich, Wako Pure Chemical Industry, Osaka, Japan) at pH 7.2 (adjusted before sterilization). The test tubes were shaken on a reciprocal shaker (320 r.p.m.) at 27 1C for 2 days. Aliquots (2.5 ml) of the broth were transferred to 500-ml baffled Erlenmeyer flasks containing 100 ml of a production medium consisting of 2.0% glycerol (Nacalai Tesque, Kyoto, Japan), 1.0% molasses (Dai-Nippon Meiji Sugar), 0.5% casein (Kanto Chemical, Tokyo, Japan), 0.1% polypeptone (Nihon Pharmaceutical) and 0.4% CaCO 3 (Kozaki Pharmaceutical, Tokyo, Japan) at pH 7.2 (adjusted before sterilization), and were cultured on a rotary shaker (180 r.p.m.) at 27 1C for 5 days.The fermentation broth (2 l) was separated by centrifugation. The supernatant was partitioned between EtOAc and H 2 O (2lÂ 3), whereas the mycelial cake was extracted with acetone (50 ml) and filtered, and the filtrate was concentrated in vacuo. The residual aqueous concentrate was extracted with EtOAc (equal volume Â 3). The combined EtOAc layers were dried over Na 2 SO 4 , and then evaporated to dryness. The residue (733 mg) was subjected to normalphase medium pressure liquid chromatography (Purif-Pack SI-30, Shoko Scientific, Yokohama, Japan) and developed successively with a gradient system of n-hexane-EtOAc (0-15% E...

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Novel antibiotics, furaquinocins C, D, E, F, G and H.

Cited by 60 publications

References 7 publications

Biosynthesis of a Natural Polyketide-Isoprenoid Hybrid Compound, Furaquinocin A: Identification and Heterologous Expression of the Gene Cluster

Biosynthesis of a Natural Polyketide-Isoprenoid Hybrid Compound, Furaquinocin A: Identification and Heterologous Expression of the Gene Cluster

Furaquinocins I and J: novel polyketide isoprenoid hybrid compounds from Streptomyces reveromyceticus SN-593

A new furaquinocin derivative, JBIR-136, from Streptomyces sp. 4963H2

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