WS009 A and B, new endothelin receptor antagonists isolated from Streptomyces sp. No. 89009. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities.

Miyata, Susumu; Ohhata, Nobutaka; Murai, Hidetsugu; Masui, Yuko; Ezaki, Masami; Takase, Shigehiro; Nishikawa, Motoaki; Kiyoto, Sumio; Okuhara, Masakuni; Kohsaka, Masanobu

doi:10.7164/antibiotics.45.1029

Cited by 26 publications

(14 citation statements)

References 26 publications

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“…Sulfur substitution at C-6a is reported for potent endothelin receptor antagonists WS009A and B (FR901366 and FR901367), where an N-acetylcysteine moiety is present at C-6a. [11,12] Moreover, the angucycline part of 2 only differs from WS009B in the hydroxylation pattern: in WS009B the C-6 position is hydroxylated, and in 2 the C-5 position bears the oxygen atom and sugar moieties are attached. The structures of WS009A and B do not contain any sugar units and the absolute configuration is not reported.…”

Section: Discussionmentioning

confidence: 99%

Grecocyclines: New Angucyclines from Streptomyces sp. Acta 1362

et al. 2010

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Section: Discussionmentioning

confidence: 99%

Grecocyclines: New Angucyclines from Streptomyces sp. Acta 1362

et al. 2010

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“…In streptomyces MSH appears to detoxify and protect the cell from a variety of endogenously generated antibiotics and reactive intermediates, as evidenced by the isolation of mercapturic acids from fermentation broths (2,5,12). It is proposed that mycobacteria retain this capability and can similarly detoxify exogenously supplied antibiotics using MSH and the MSH S-conjugate amidase.…”

Section: Discussionmentioning

confidence: 99%

“…It seems likely that this mechanism is also involved in self-detoxification of antibiotics that are produced by fermentation broths of several antibiotic-producing microorganisms and that have been found to be remarkably nontoxic. For example, the polyketide antibiotic derivatives cysfluoretin (2) and WS009A and WS009B (12), produced in Streptomyces spp., were found to be nontoxic compared to the toxicities of compounds with related structures but lacking the N-acetylcysteine moiety when they were tested in vitro and in vivo. Gould and colleagues (5) expressed an ϳ40-kb fragment of the polyketide kinamycin biosynthesis gene cluster in the heterologous host (14) and likely would have the MSH S-conjugate amidase activity (15) required to produce the mercapturic acid derivative and allow its excretion into the fermentation broth, as was observed (5).…”

Section: Discussionmentioning

confidence: 99%

Mycothiol-Deficient Mycobacterium smegmatis Mutants Are Hypersensitive to Alkylating Agents, Free Radicals, and Antibiotics

Rawat

Newton

et al. 2002

Antimicrob Agents Chemother

184

201

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Mycothiol (MSH; 1D-myo-inosityl 2-[N-acetyl-L-cysteinyl]amido-2-deoxy-␣-D-glucopyranoside) is the major low-molecular-weight thiol produced by mycobacteria. Mutants of Mycobacterium smegmatis mc2 155 deficient in MSH production were produced by chemical mutagenesis as well as by transposon mutagenesis. One chemical mutant (mutant I64) and two transposon mutants (mutants Tn1 and Tn2) stably deficient in MSH production were isolated by screening for reduced levels of MSH content. The MSH contents of transposon mutants Tn1 and Tn2 were found to be less than 0.1% that of the parent strain, and the MSH content of I64 was found to be 1 to 5% that of the parent strain. All three strains accumulated 1D-myo-inosityl 2-deoxy-␣-D-glucopyranoside to levels 20-to 25-fold the level found in the parent strain. The cysteine:1D-myo-inosityl 2-amino-2-deoxy-␣-D-glucopyranoside ligase (MshC) activities of the three mutant strains were <2% that of the parent strain. Phenotypic analysis revealed that these MSH-deficient mutants possess increased susceptibilities to free radicals and alkylating agents and to a wide range of antibiotics including erythromycin, azithromycin, vancomycin, penicillin G, rifamycin, and rifampin. Conversely, the mutants possess at least 200-fold higher levels of resistance to isoniazid than the wild type. We mapped the mutation in the chemical mutant by sequencing the mshC gene and showed that a single amino acid substitution (L205P) is responsible for reduced MSH production and its associated phenotype. Our results demonstrate that there is a direct correlation between MSH depletion and enhanced sensitivity to toxins and antibiotics. Fig. 1A) is a low-molecular-weight thiol that serves functions in mycobacteria analogous to those of glutathione in gram-negative bacteria and eukaryotes (7). These functions include protection against oxidative damage and inactivation of electrophilic toxins (15,17). The distribution of MSH is limited to gram-positive actinomycetes, and of all the species tested, mycobacteria appear to generate the highest levels of MSH (14). The absence of MSH in mammalian cells suggests that the enzymes involved in the metabolism of MSH may be attractive drug targets for either rational drug design or screening of libraries of inhibitory compounds (25). Mycothiol (MSH;Although studies of MSH biosynthesis are still at an early stage, as shown in Fig. 1B, elements of the overall pathway have been described (1, 4, 16). Moreover, direct measurements of intermediates in bacterial extracts that support the proposed biosynthetic pathway have been reported (1). The genes for the MSH biosynthesis pathway were designated mshA, mshB, mshC, and mshD (16), with the corresponding enzymes labeled as shown in Fig. 1. It has been shown that 1D-myo-inosityl 2-acetamino-2-deoxy-␣-D-glucopyranoside (GlcNAc-Ins) is an intermediate (16), and we presume that its formation is the first dedicated step in MSH biosynthesis. Glucosaminylinositol is formed by deacetylation of GlcNAc-Ins. We have previously identified m...

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“…As to classification of angucycline and angucyclinone, the former includes those with hydrolysable sugar moieties, while the latter refers to a sugarless compound. There are ample reports that these antibiotics have various biological actions, including antitumor activity (27)(28)(29)(30)(31)(32). Landomycins belong to angucycline antibiotics with sugar moieties and have promising antitumor activities in vitro and in vivo (33).…”

Section: Discussionmentioning

confidence: 99%

Induction of apoptosis by the angucyclinone antibiotic chemomicin in human tumor cells

He¹

2009

Oncol Rep

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Abstract. Chemomicin (CHM), an angucyclinone antibiotic extracted from the fermentation broth of Nocardia Mediterranei subsp. Kanglensis 1747-64, shows immunosuppressive activity. However, whether it can inhibit growth of tumor cells remains elusive. In the present study, we show that CHM potently inhibited the proliferations of eight various types of human tumor cell lines and non-cross resistant to multidrugresistant cells. In contrast to action of doxorubicin, the generation of reactive oxygen species was observed as early as 30 min after addition of CHM and its process did not involve iron. The apoptotic cells with chromatin condensation and Annexin V staining markedly increased after the human hepatoma HepG2 was exposed to 1, or 2 μg/ml CHM for 24 h. In the CHM-induced apoptosis, robust increment of p53 expression, activation of caspase-3, -7, -8, -9, cleavage of PARP and the phosphorylation of p38 and JNK, were detected by Western blot analysis. Further investigation revealed the disruption of mitochondrial membrane potential in the cells with CHM incubation for 4 h. Taken together, the results demonstrated that potent proliferation inhibitory effect of CHM on tumor cells is due to activation of the apoptotic pathway.

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WS009 A and B, new endothelin receptor antagonists isolated from Streptomyces sp. No. 89009. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities.

Cited by 26 publications

References 26 publications

Grecocyclines: New Angucyclines from Streptomyces sp. Acta 1362

Grecocyclines: New Angucyclines from Streptomyces sp. Acta 1362

Mycothiol-Deficient Mycobacterium smegmatis Mutants Are Hypersensitive to Alkylating Agents, Free Radicals, and Antibiotics

Induction of apoptosis by the angucyclinone antibiotic chemomicin in human tumor cells

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