Novel antibiotics, furaquinocins A and B. Taxonomy, fermentation, isolation and physico-chemical and biological characteristics.

Abstract

Two novel antibiotics, furaquinocins A and B were isolated from the culture broth of Streptomyces sp. . These antibiotics possess cytocidal activities against HeLa S3 cells in vitro at concentrations of 3.1/xg/ml for A and 1.6/zg/ml for B. Neither substance possessed antimicrobial activities against Gram-positive and Gram-negative bacteria, fungi or yeast at a concentration of 1 ,000 /ig/ml.In the course of a screening program for novel antibiotics showing cytocidal activities, a fraction of the fermentation broth of Streptomyces sp. KO-3988, which had been isolated from a soil sample collected in Shizuoka Prefecture, Japan, showed potent cytocidal activity. Twoactive components designated as furaquinocins A and B were obtained from the culture broth of this microorganism.The present paper deals with the taxonomic studies of the producing strain, and the production, isolation and physico-chemical properties of the new antibiotics. The preliminarily biological activities of furaquinocins against HeLaS3 cells and various microorganismsare also described. Materials and Methods General Experimental ProceduresMP's were determined using a YanagimotoMP-3hot stage microscope and are uncorrected. UV spectra were recorded on a Shimadzumodel UV-200Sspectrophotometer. IR spectra were recorded on a Jasco model A-102 interferometer. Mass spectra were obtained with a Jeol model DX-300mass spectrometer. 1H and 13C NMRspectra were recorded on a Varian XL-400 instrument. Kieselgel 60 (Merck), Diaion HP-20 (Mitsubishi Chemical Industries) and Sephadex LH-20 (Pharmacia Fine Chemicals) were used for column chromatography and DC-Fertigplatten Kieselgel 60 (Merck) was used for TLC analysis and for preparative TLC.Taxonomic Studies Type of diaminopimelic acid (DAP) was determined by the method of Takahashi et al}\ To investigate the cultural and physiological characteristics, the International Streptomyces Project (ISP) media recommended by Shirling and Gottlieb2) and those recommended by Waksman3) were used. Cultures were observed after incubation at 27°C for 2 weeks. Color namesand hue numbers indicated in Table 1 are those of Color HarmonyManual (4th Ed.)4). The utilization of carbon sources was tested by growth on Pridham and Gottlieb's medium5) containing 1%carbon source at 27°C.Anti HeLa S3 Tests HeLa S3 cells were maintained in monolayers in Eagle's minimumessential medium (MEM) supplemented with 10% bovine serum and an antibiotic (60 /ig/ml of kanamycin) at 37°C.

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

“…We detected one specific compound ( Fig. 3) which was eluted with almost the same retention time as authentic FQ A and has almost the same UV spectrum as FQ A (23). We attempted to purify the compound; however, we could not prepare a sufficient quantity of the compound for structural analysis because of its low productivity.…”

“…These moieties are biosynthesized via pathways independent of isoprenoids to further give rise to the so-called isoprenoidhybrid compounds, such as novobiocin (27), clorobiocin (27), brasilicardin A (22), KS505a (31), and lavanducyanin (16). Moreover, several actinomycete strains are known to produce polyketide-isoprenoid hybrid compounds, such as furaquinocin (FQ) (23), naphterpin (38), napyradiomycin (40), and marinone (33), all of which were reported to show biological activities and could act as an antitumor drug, an antioxidative agent, a nonsteroidal estrogen receptor antagonist, and an anticancer drug, respectively. Considering that the structures of polyketide moieties, which are derived from 1,3,6,8-tetrahydroxynaphthalene (THN), are almost the same in these compounds, the prenyl moieties are suggested to play important roles in exhibiting diversity in the biological activities of these compounds.…”

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

“…[8][9][10] FQs, originally isolated from the culture broth of Streptomyces sp. 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.…”

“…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.…”

Regiospecificities and Prenylation Mode Specificities of the Fungal Indole Diterpene Prenyltransferases AtmD and PaxD

“…For example, the presence of isoprenoid chains of various lengths and types is a major determinant of the bioactivity of prenylated flavonoids (12)(13)(14). The polyketide-isoprenoid hybrid compounds furaquinocin, naphterpin, marinone, and napyradiomycin have been reported to have antitumor (15), antioxidative (16), and anticancer (17) activities and to act as a nonsteroidal estrogen receptor antagonist (18), respectively. These molecules have similar polyketide moieties derived from 1,3,6,8-tetrahydroxynaphthalene (THN), showing that prenyl moieties play important roles in providing diverse biological activities.…”