Yong-Pil Kim

Suppression of bone resorption by madindoline A, a novel nonpeptide antagonist to gp130

IL-6 is a multifunctional cytokine involved in regulation of differentiation, antibody production, and growth of certain types of tumor cells. Its excessive production plays a major role in pathogenesis of multiple myeloma and postmenopausal osteoporosis. In the course of a screening program aimed at IL-6 inhibitor from microbial products, we found madindoline A (MDL-A) and madindoline B, which have a fuloindoline structure with diketocyclopentene bound to the methyl group. MDL-A has no cytotoxic activities. It inhibited only activities of both IL-6 and IL-11 without affecting the IL-6-specific signal transduction cascade, JAK2/STAT3. In a dose-dependent manner [3H]MDL-A binds to gp130, which is a signal transducing 130-kDa glycoprotein, but formation of the trimeric complex IL-6/IL-6 receptor/gp130 was not inhibited, suggesting that MDL-A suppresses dimerization of trimeric complexes. Not only did MDL-A markedly inhibit IL-6- and IL-11-induced osteoclastogenesis in vitro, but it also inhibited IL-6-stimulated serum amyloid A production and bone resorption in an experimental model of postmenopausal osteoporosis in vivo by a different mechanism from that of 17β-estradiol. Here we show that MDL-A has a highly selective inhibitory effect on IL-6 and IL-11 activities by inhibiting a gp130 activity while suppressing bone loss in ovariectomized mice. MDL-A is anticipated as a lead compound for treatment of hormone-dependent postmenopausal osteoporosis, which has no serious side effects, and as a new mechanism of action, gp130 blocking.

Cyslabdan, a New Potentiator of Imipenem Activity against Methicillin-resistant Staphylococcus aureus, Produced by Streptomyces sp. K04-0144 : II. Biological Activities

AbstractCyslabdan produced by Streptomyces sp. K04-0144 was found to potentiate imipenem activity against methicillin-resistant Staphylococcus aureus (MRSA). The MIC value of imipenem against MRSA was reduced from 16 to 0.015 μg/ml in combination with cyslabdan. Study on anti-MRSA activity of other typical antibiotics in combination with cyslabdan showed that the potentiating activity was limited to β-lactam antibiotics. Furthermore, among β-lactam antibiotics, the activity of carbapenems was most remarkably poteintiated by cyslabdan.

Cyslabdan, a New Potentiator of Imipenem Activity against Methicillin-resistant Staphylococcus aureus, Produced by Streptomyces sp. K04-0144 I. Taxonomy, Fermentation, Isolation and Structural Elucidation

AbstractCyslabdan, a new potentiator of imipenem activity against methicillin-resistant Staphylococcus aureus, was isolated from the culture broth of Streptomyces sp. K04-0144 by Diaion HP-20 and ODS column chromatographies and preparative HPLC. The structure of cyslabdan was elucidated by spectroscopic analyses including NMR. The compound has a labdane-type diterpene skeleton connecting with an N-acetylcysteine via thioether linkage.

Guadinomines, Type III secretion system inhibitors, produced by Streptomyces sp. K01-0509. II: physico-chemical properties and structure elucidation.

The structures of guadinomines, new inhibitors of a bacterial Type III secretion system produced by Streptomyces sp. K01-0509, were elucidated by spectroscopic studies including various NMR experiments. Guadinomines A, B, C1, C2 and D consist of a carbamoylated cyclic guanidinyl moiety, an alkyl chain moiety and an L-Ala-L-Val moiety in common, while guadinomic acid is a smaller molecule consisting of a carbamoylated cyclic guanidinyl moiety and a hydroxyl hexanoate moiety.

Nosokomycins, new antibiotics discovered in an in vivo-mimic infection model using silkworm larvae. I: Fermentation, isolation and biological properties.

The in vivo-mimic assay system using silkworm larvae was used as a screening tool to discover antibiotics against methicillin-resistant Staphylococcus aureus (MRSA). Microbial culture broths were screened in this in vivo-mimic assay system and a culture broth of Streptomyces sp. K04-0144 was selected. New antibiotics, designated nosokomycins A–D, were isolated from the culture broth by HP-20 and ODS column chromatography and HPLC. Nosokomycins inhibited the growth of MRSA with MIC values of 0.125 μg ml−1 using the liquid microdilution method. Furthermore, MRSA-infected silkworms survived when nosokomycin A or B was injected at a dose of 50 μg per larva.

Sespendole, a New Inhibitor of Lipid Droplet Synthesis in Macrophages, Produced by Pseudobotrytis terrestris FKA-25

Sespendole was isolated as an inhibitor of lipid droplet formation in macrophages from the culture broth of a fungal strain Pseudobotrytis terrestris FKA-25. The compound inhibited the synthesis of cholesteryl ester and triacylglycerol by mouse macrophages with IC50 values of 4.0 and 3.2 µM, respectively.

Taxonomy and secondary metabolites of Pseudobotrytis sp. FKA-25

Fungal strain FKA-25, isolated from forest soil collected on Yakushima Island, Kagoshima Prefecture, Japan, was assigned to genus Pseudobotrytis based on its morphological characteristics. Conidiophores were erect, slightly swollen at the end of the tip, and gave rise to umbellate conidiogenous cells that were in an expanded denticulate portion at the end and formed ellipsoidal to clavate conidia in sympodial succession. Identification as species P. terrestris was made on the basis of the character of 1-septate conidium. Although no secondary metabolites have been reported from the genus Pseudobotrytis, four secondary metabolite compounds (designated A to D) were isolated from the culture broth of strain FKA-25. Compounds B to D have been reported previously as FK-17-p2a, lunatinin, and 3,4-dihydro-3,4,8-trihydroxy-1(2H)-naphthalenone, respectively. Compound A was designated sespendole and possessed a novel indole-sesquiterpene skeleton.

Nosokomycins, new antibiotics discovered in an in vivo-mimic infection model using silkworm larvae. II: Structure elucidation.

The structures of nosokomycins A, B, C and D, new anti-methicillin-resistant Staphylococcus aureus antibiotics produced by Streptomyces sp. K04-0144, were elucidated by spectroscopic studies including various NMR experiments. Nosokomycins A, B, C and D are new members of the moenomycin family consisting of an oligosaccharide moiety, a 2,3-dihydroxypropionic acid and an unusual sesterterpenoid moiety. All nosokomycins lack the cyclopentenone moiety in the oligosaccharide moiety of moenomycin A.

Structure Elucidation of Fungal Sespendole, an Inhibitor of Lipid Droplet Synthesis in Macrophages

A new fungal metabolite named sespendole was isolated as an inhibitor of lipid droplet synthesis in mouse macrophages from the culture broth of the fungal strain Pseudobotrytis terrestris FKA-25. The structure and stereochemistry of sespendole were elucidated by spectroscopic studies including various NMR spectral analyses, exciton chirality experiments and the modified Mosher method. Sespendole was found to possess a new indolosesquiterpene skeleton modified with two isoprenes.

Naphthacemycins, novel circumventors of .BETA.-lactam resistance in MRSA, produced by Streptomyces sp. KB-3346-5. I. The taxonomy of the producing strain, and the fermentation, isolation and antibacterial activities

Screening for circumventors of β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) led us to find 17 novel antibiotics, naphthacemycins A1–A11, B1–B4 and C1–C2. The naphthacemycins were isolated from a cultured broth of Streptomyces sp. KB-3346-5 by repeated silica gel column chromatography and HPLC. Naphthacemycins enhanced imipenem activity 100–500 times against MRSA at 0.5 μg ml−1, and naphthacemycins A4–A11 themselves showed MIC50 values of 1–4 μg ml−1 against 22 MRSA strains.