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

Abstract

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.

Development of a Terpenoid-Production Platform in Streptomyces reveromyceticus SN-593

“…In fact, specialized terpenoid production mainly correlated with an operation of the mevalonate gene cluster and the associated target terpenoid biosynthetic genes at a late stage of growth. 31 In the present study, we have focused on the potential of Streptomyces reveromyceticus SN-593 32,33 because it produces 1 g/L of reveromycins (RMs) by up-regulation of a pathway specific regulator. 34 In addition, the strain possesses a furaquinocin (FQ) gene cluster 35 associated with a mevalonate gene cluster.…”

Meroterpenoid natural products fromStreptomycesbacteria – the evolution of chemoenzymatic syntheses

“…The C-3 geranyl group of the napyradiomycins can also undergo oxidation and macrocyclisation, usually at the C-7 position of the aromatic ring, to form highly complex natural products such as napyradiomycin C1 (48) (Figure 5). Napyradiomycins C1 (48) and C2 (49) were isolated from a culture broth of S. rubra MG802-AF1, 13 and were found to inhibit the growth of Gram-positive bacteria including multiple drug-resistant strains such as S. aureus MS8710 and MS9610. 16-Dechloro-16-hydroxy-napyradiomycin C2 (50) was isolated from the culture broth of S. antimycoticus NT17.…”

“…Furaquinocins I (90) and J (91) were isolated in 2011 from Streptomyces reveromyceticus SN-593 strain NRM2. 48 PI-220 (92) was isolated from the culture broth of Streptomyces sp. A8059.…”

β-carboline chemical signals induce reveromycin production through a LuxR family regulator in Streptomyces sp. SN-593

“…The vector was then transformed into Streptomyces sp. SN-593 by conjugal gene transfer 24,49 . Gene disruption was confirmed by Southern hybridization.…”