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MASAHISA OKA, SEIJI IIMURA, OSAMU TENMYO, YOSUKE SAWADA, MASARU SUGAWA ...
1993 Volume 46 Issue 3 Pages
367-373
Published: March 25, 1993
Released on J-STAGE: April 19, 2006
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Terpestacin, a new antibiotic which inhibits syncytium formation, was isolated from
Arthrinium sp. FA1744 (ATCC 74132). The structure of terpestacin was elucidated as a bicyclic sesterterpene on the basis of spectroscopic data and chemical derivatization.
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I. TAXONOMY AND FERMENTATION OF THE PRODUCING ORGANISM AND BIOLOGICAL ACTIVITY
JAMES P. KARWOWSKI, MARIANNA JACKSON, RONALD R. RASMUSSEN, PATRICK E. ...
1993 Volume 46 Issue 3 Pages
374-379
Published: March 25, 1993
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The ardeemins are a new family of secondary metabolites produced by submerged fermentation of a fungus which was isolated from a soil sample collected in Brazil. Based on taxonomic studies, the producing culture was identified as
Aspergillus fischeri var.
brasiliensis strain AB 1826M-35. 5-
N-Acetylardeemin potentiated the cytotoxicity of the anticancer agent vinblastine in multidrug resistant human tumor cells.
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II. ISOLATION AND ELUCIDATION OF THE STRUCTURE OF 5-N-ACETYLARDEEMIN AND TWO CONGENERS
JILL E. HOCHLOWSKI, MARK M. MULLALLY, STEPHEN G. SPANTON, DAVID N. WHI ...
1993 Volume 46 Issue 3 Pages
380-386
Published: March 25, 1993
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A family of novel compounds has been detected and isolated following an assay for the attenuation of multiple drug resistance in tumor cells from the fermentation broth and mycelia of a strain of
Aspergillus fischeri which we have designated var.
brasiliensis. The structures of three components were determined employing 1-D and 2-D homonuclear and heteronuclear NMR spectroscopy and mass spectrometry. The structure of 5-
N-acetylardeemin was confirmed by single crystal X-ray diffraction. These compounds are most closely structurally related to asnerlicin E
1)
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KYOICHIRO SAITOH, YOSUKE SAWADA, KOJI TOMITA, TAKASHI TSUNO, MASAMI HA ...
1993 Volume 46 Issue 3 Pages
387-397
Published: March 25, 1993
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Pradimicin L, a new congener of pradimicin A having the D-glucosyl-D-thomosamine moiety at the C-5 position, was isolated from
Actinomadura verrucosospora subsp.
neohibisca subsp. nov. The structure of pradimicin L was deduced to be
N-[[(5
S, 6
S)-5-
O-[4, 6-dideoxy-4-(methylamino)-3-
O-(β-D-glucopyranosyl)-β-D-galactopyranosyl]-5, 6, 8, 13-tetrahydro-1, 5, 6, 9.14-pentahydroxyll-methoxy-3methyl-8, 13-dioxobenzo[
a]naphthacene-2 yl]carthonyl]-D-alanime by MS and NMR spectrometry and degradation studies. Pradimicin FL which has the D-serine moiety instead of D-alanine was produced by directed biosynthesis in D-serine-supplemented medium. Pradimicins L and FL have a broad spectrum of
in vitro antifungal activity. Pradimicin L was equiactive to pradimicin A and pradimicin FL was more active than pradimicin L.
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KYOICHIRO SAITOH, KIYOSHI SUZUKI, MINORU HIRANO, TAMOTSU FURUMAI, TOSH ...
1993 Volume 46 Issue 3 Pages
398-405
Published: March 25, 1993
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Exogenous addition of D-serine to
Actinomadura spinosa AA0851 resulted in directed production of pradimicin FS, a new D-serine analog of pradimicin S, together with pradimicin FB. Pradimicin FS was produced in higher yields by derivation of ferrous sulfate-resistant strains from strain AA0851. Pradimicin FB, a minor product, was identified as deglucosylpradimicin FL. Pradimicin FS was equivalent to pradimicin S in syncytium formation inhibition activity and
in vitro and
in vivo antifungal activities.
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II. ISOLATION AND STRUCTURE ELUCIDATION
KYOICHIRO SAITOH, TAKASHI TSUNO, MASATOSHI KAKUSHIMA, MASAMI HATORI, T ...
1993 Volume 46 Issue 3 Pages
406-411
Published: March 25, 1993
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Pradimicin S was isolated from the culture nitrate of
Actinomadura spinosa AA0851. NMR and MS analyses proved that pradimicin S is the 3'-
O-(3"-
O-sulfo-β-D-glucopyranosyl) analog of pradimicin A, a new member of the pradimicin family of antibiotics. Stereochemical assignment was made by correlating pradimicin S with pradimicin L.
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I. GENERATION AND SELECTION OF PRADIMICIN-NONPRODUCING MUTANTS
TAMOTSU FURUMAI, SHIZUKO KAKINUMA, HARUAKI YAMAMOTO, NOBUJIRO KOMIYAMA ...
1993 Volume 46 Issue 3 Pages
412-419
Published: March 25, 1993
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Germinated spores of
Actinomadura verrucosospora subsp.
neohibisca E-40, a high pradimicins producer, were mutagenized by
N-methyl-
N'-nitro-
N-nitrosoguanidine and/or UV treatment. Thirty-seven mutants which did not produce pradimicin were selected to test for cosynthesis ability, and classified into nine classes. On the basis of their cosynthesis ability and bioconversion results, we concluded that strain JN-213 (class III) was a true converter and that strains JN-219 (class IV), JN-47 (class V) and JNU-46 (class VI) were secretors accumulating biosynthetic intermediates of pradimicin, and that strains JN-59 (class VII), JN-58 (class VIII) and JN-207 (class IX) were producers of shunt metabolites of pradimicin biosynthesis. TLC and HPLC analyses of the fermentation broths of individual strains showed that 8 new compounds were produced along with pradinone I, pradimicinone I, 11-
O-demethylpradimicinone II and 7-
O-methylpradimicinone II.
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II. FERMENTATION, ISOLATION AND STRUCTURE DETERMINATION OF METABOLITES ASSOCIATED WITH THE PRADIMICINS BIOSYNTHESIS
TAKASHI TSUNO, HARUAKI YAMAMOTO, YUKIO NARITA, KIYOSHI SUZUKI, TOSHIFU ...
1993 Volume 46 Issue 3 Pages
420-429
Published: March 25, 1993
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Ten metabolites produced by 4 mutants derived from
Actinomadura verrucosospora subsp.
neohibisca E-40, a high pradimicins producer, were isolated and their structures were determined. Strain JN-219 produced 3 novel analogs of the pradimicin A aglycone,
i.e. 11-
O-demethyl-7-methoxypradinone II and 11-
O-demethylpradinones I and II together with a known aglycone analog, pradinone I, while the metabolites from strain JN-47 were determined to be 2 new aglycone analogs, 11-
O-demethylpradimicinone I and 11-
O-demethyl-7-methoxypradimicinone II and a known aglycone analog, 11-
O-demethylpradimicinone II (11dM-PMN II). Products of strain JN-207 were identified as 11-
O-demethyl-6-deoxypradinone I and 11dM-PMN II. Interestingly, a new pradimicin analog, 7-hydroxypradimicin A was isolated from strain JN-58 together with a new aglycone analog, pradimicinone II and 11dM-PMN II. None of these metabolites showed antifungal activity.
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III. BIOSYNTHETIC PATHWAY OF BOTH PRADIMICINS AND BENANOMICINS
SHIZUKO KAKINUMA, KIYOSHI SUZUKI, MASAMI HATORI, KYOICHIRO SAITOH, TOS ...
1993 Volume 46 Issue 3 Pages
430-440
Published: March 25, 1993
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The biosynthetic pathway of the pradimicin-benanomicin family of antibiotics was investigated by using sinefungin and blocked mutants derived from
Actinomadura verrucosospora subsp.
neohibisca E-40 (a high pradimicin producer) or
Actinomadura sp. AB1236 (a benanomicin producer). Addition of sinefungin to strain E-40, pradimicin A aglycone-producing mutant or strain AB1236 inhibited the formation of 11-
O-demethyl-7-methoxypradinone II (11dM-7M-PN II), resulting in the accumulation of 11-
O-demethylpradimicinone II and pradimicinone II. By feeding pradimicin A aglycone and its analogs to mutants blocked early in pradimicin or benanomicin biosynthesis, the following results were obtained: 11-
O-demethylpradinone II, 11dM-7M-PN II, 11-
O-demethylpradinone I, 11-
O-demethylpradimicinone I and pradimicinone I were converted to pradimicin A or benanomicin A; the remaining 6 aglycone analogs were not incorporated into the antibiotics. Pradimicin B, dexylosylpradimicin C and dexylosylbenanomicin A were converted to pradimicin A, pradimicin C and benanomicin A, respectively. A biosynthetic pathway for the antibiotics is proposed.
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SIRI RAM CHHABRA, PAUL STEAD, NIGEL J. BAINTON, GEORGE P. C. SALMOND, ...
1993 Volume 46 Issue 3 Pages
441-454
Published: March 25, 1993
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N-(3-Oxohexanoyl)-L-homoserine lactone (HSL) (I) is the autoregulator controlling carbapenem antibiotic biosynthesis in
Erwinia carotovora ATCC 39048. The chemical synthesis and biological evaluation of analogues of HSL are described. These include alterations of chirality, side-chain modifications, ring size and ring hetero atom. A number of compounds are reported which are capable of restoring the phenotype to a HSL negative mutant but at higher concentrations than HSL.
A-factor, the autoregulator of streptomycin biosynthesis in
Streptomyces griseus, was not active as an inducer of carbapenem biosynthesis in
E. carotovora.
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II. D-MANNOPYRANOSIDE-BINDING SITE AND CALCIUM-BINDING SITE
TOMOKAZU UEKI, KEI-ICHI NUMATA, YOSUKE SAWADA, MAKI NISHIO, HIROAKI OH ...
1993 Volume 46 Issue 3 Pages
455-464
Published: March 25, 1993
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Based on the structure-activity relationship data of BMY-28864 and related pradimicin derivatives, the calcium salt-forming ability and the D-mannopyranoside-specific visible absorption maximum shift of BMY-28864 were analysed in the ternary complex forrnation of BMY-28864 with D-mannopyranoside and calcium. The free C-18 carboxyl group of BMY-28864 was proved to be the sole site for binding to calcium, while no hydroxyl groups of the aglycone were involved in calcium salt formation. The stereo specific D-mannopyranoside-recognizing ability of BMY-28864 was completely abolished by removal of the C-5 disaccharide moiety, and, more particularly, of the C-5 thomosamine moiety. Close relationship of these findings with the antifungal action was also supported by the
in vitro antifungal assay and the potassium leakage induction test.
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III. SPECTROPHOTOMETRIC SEQUENCE ANALYSIS OF THE TERNARY COMPLEX FORMATION OF BMY-28864 WITH D-MANNOPYRANOSIDE AND CALCIUM
TOMOKAZU UEKI, MASAHISA OKA, YASUO FUKAGAWA, TOSHIKAZU OKI
1993 Volume 46 Issue 3 Pages
465-477
Published: March 25, 1993
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Sequence of reactions in the process of ternary complex formation of BMY-28864 with D-mannopyranoside and calcium was spectrophotometrically determined under more strict analytical conditions using metal-free preparations of sugars and the pradimicin derivative at a bandpass slit width of 1 nm. In the first phase of ternary complex formation, BMY-28864 stereo specifically recognized and bound to D-mannopyranoside in the absence of calcium, which was revealed by a visible absorption maximum shift of
ca. 8 nm. Subsequently, the BMY-28864-D-mannopyranoside conjugate reacted with calcium to yield the ternary complex, which was detected by an additional visible absorption maximum shift of
ca. 8 nm. When the three components were mixed at the same time, both phases simultaneously occurred to produce the ternary complex which was accompanied by a visible absorption maximum shift of 16nm in total. Based on this two-phased reaction sequence, the mechanism of ternary complex formation .of BMY-28864 with D-mannopyranoside and calcium was reexamined in details. Terminal D-mannopyranoside was confirmed to be essential as BMY-28864-specific sugar receptor by
in vitro analysis and animal cell experiments. While calcium, strontium and cadmium behaved similar in the
in vitro ternary complex formation, the yeast and animal cell experiments showed that only calcium played a dual role as a base in the ternary complex formation and as an effector in physiological disturbances leading to cell death.
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KIKUTAROU ENDOU, MAYUMI MATSUOKA, HIROFUMI TANIGUCHI, YOSHINORI NAKAJI ...
1993 Volume 46 Issue 3 Pages
478-485
Published: March 25, 1993
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In a previous paper we reported that rokitamycin (RKM) which killed some types of RKM-susceptible staphylococci bound cohesively to ribosomes obtained from such bacteria whereas other macrolides such as erythromycin and josamycin, which are generally known to be bacteriostatic, bound to these ribosomes only reversibly. From this observation, we speculated that such cohesive binding of RKM to certain ribosomes probably resulted in cell killing (ENDOU, K.
et al., FEMS Microbiology Letters, 72: 93-96, 1990). However, this speculation was based only on circumstantial evidence and we did not show directly that reversible binding of RKM to ribosomes from other strains would bring about bacteriostasis only. A clinically isolated strain,
Staphylococcus aureus S704, was found to be susceptible to RKM, mycinamicin and tylosin as well as lincosamide and streptogramin type B antibiotics but not to other macrolides (erythromycin, josamycin, rosamicin,
etc.). RKM showed bacteriostatic, but not bactericidal activity, on the strain. Determinant(s) responsible for the bacteriostatic phenotype was transferred into strain NCTC8325 using bacteriophage 80L2; the obtained transductant was referred to as strain 8325MMT7. The drug bound reversibly, not cohesively, to the ribosomes from both strains S704 and 8325MMT7, confirming our earlier hypothesis that rokitamycin can cause bacteriostasis or cell death depending upon whether it binds reversibly or cohesively to the ribosomes of a given strain.
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ANDREW W. TAYLOR, BENJAMIN J. COSTELLO, PAMELA A. HUNTER, WILLIAM S. M ...
1993 Volume 46 Issue 3 Pages
486-493
Published: March 25, 1993
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The syntheses of the first amphotericin B derivatives to be modified solely at the C-13 hemiketal position are described. Selective functionalisation at this position is facilitated by use of the allyl ester as a C-16 carboxylate protecting group on the amphotericin B nucleus. In
in vitro tests all compounds showed markedly reduced haemolytic activity against mammalian erythrocytes while two of the novel 13-alkoxy derivatives retained good antifungal activity.
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MAKI NISHIO, HIROAKI OHKUMA, MASATOSHI KAKUSHIMA, SHIN-ICHI OHTA, SEUI ...
1993 Volume 46 Issue 3 Pages
494-499
Published: March 25, 1993
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Chemical modifications of the carboxyl group in the alanine moiety of pradimicin A were performed and
in vitro and
in vivo antifungal activities of the derivatives were examined in comparison with those of pradimicin A. The amide derivatives showed activities comparable to pradimicin A, indicating that the free carboxyl group can be modified without impairing the antifungal activity.
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SATSUKI OKUYAMA, MASATOSHI KAKUSHIMA, HAJIME KAMACHI, MASATAKA KONISHI ...
1993 Volume 46 Issue 3 Pages
500-506
Published: March 25, 1993
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A series of pradimicin analogs were designed and synthesized to investigate the effect of the amino acid side chain on the antifungal activity. The alanine-exchanged analogs (
3a-
3q) were synthesized from 4'-
N-Cbz-pradimic acid by coupling with appropriate amino acids or their equivalents followed by deblocking. All the D-α-amino acid derivatives except D-proline analog,
3k retained the antifungal activity.
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YOSUKE SAWADA, TAKASHI TSUNO, TOMOKAZU UEKI, HARUAKI YAMAMOTO, YASUO F ...
1993 Volume 46 Issue 3 Pages
507-510
Published: March 25, 1993
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TOSHIO OHTA, MAMORU HASEGAWA
1993 Volume 46 Issue 3 Pages
511-517
Published: March 25, 1993
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KEIKO NAKAGAWA, KAZUO SATO, YOSHIHISA TSUKAMOTO, AKIO TORIKATA
1993 Volume 46 Issue 3 Pages
518-519
Published: March 25, 1993
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HIROSHI NAGAI, YUZURU MIKAMI, KATSUKIYO YAZAWA, TOHRU GONOI, TAKESHI Y ...
1993 Volume 46 Issue 3 Pages
520-522
Published: March 25, 1993
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PETER HAMMANN, WOLFGANG RAETHER, LASZLO VERTESY
1993 Volume 46 Issue 3 Pages
523-525
Published: March 25, 1993
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JOHN E. MCCULLOUGH, MARK T. MULLER, ALISON J. HOWELLS, ANTHONY MAXWELL ...
1993 Volume 46 Issue 3 Pages
526-530
Published: March 25, 1993
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SHINICHI KONDO, SEIJI SHIBAHARA, TAKAYUKI USUI, TOSHIAKI KUDO, ATUSHI ...
1993 Volume 46 Issue 3 Pages
531-534
Published: March 25, 1993
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