Strain S-632 was found to produce new glutarimide antibiotics, 8-632-B₁ and B₂, which were isolated from the culture fluid. A taxonomic study on strain S-632 was carried out, and the taxonomic characterization demonstrated that it belonged to the species Streptomyces hygroscopicus. The strain was given the name S. hygroscopicus S-632.
These antibiotics were active against Saccharomyces sp., but inactive against filamentous fungi and bacteria, and had cytotoxic activity against KB tissue culture cells.

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Antifungal antibiotics S-632-A₁, A₂, B₁ and B₂ were extracted with ethyl acetate from the filtered broth of Streptomyces hygroscopicus S-632 and isolated through a combination of conventional and reversed-phase silica gel column chromatography. On the basis of the spectral data, S-632-B₁ and B₂ were found to be new members of the glutarimide family of antibiotics. The chemical structures of these components were elucidated as two stereoisomers of 3-(5, 7-dimethyl-8, 9-epoxy-2-hydroxy-4-oxo-6-decenyl)glutarimide.

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A strain of actinomycetes identified as Streptomyces flavidovirens produced new antibiotics, mureidomycins (MRD's) A-D, specifically active against Pseudomonas aeruginosa. They were isolated from the culture filtrate by successive column chromatographies such as Amberlite XAD-2 and CG-50, Whatman DE-52 and Toyopearl HW-40. They were amphoteric white powders and soluble in methanol and water. Their molecular weights and molecular formulae in parentheses were 840 (C₃₈H₄₈N₈O₁₂S), 842 (C₃₈H₅₀N₈O₁₂S), 897 (C₄₀H₅₁N₉O₁₃S) and 899 (C₄₀H₅₃N₉O₁₃S), respectively. m-Tyrosine and two unknown substances were detected by amino acid analyses as their common constituents. MRD's A and C contained uracil but MRD's B and D dihydrouracil instead of uracil.

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Structures of new antibiotics, mureidomycins (MRD's) A-D, were deduced from spectroscopic analyses and degradation studies. Two residues of m-tyrosine, one residue of 2-amino-3-N-methylaminobutyric acid (AMBA) and methionine are present in all components of the complex. Uracil is contained in MRD's A and C, while dihydrouracil in MRD's B and D. Methionine and m-tyrosine are connected through an ureido bond, and uracil or dihydrouracil is linked to AMBA via enamine sugar moiety. In addition, MRD's C and D contain a glycine residue at the N-terminal.

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Mureidomycins (MRD's) A-D were specifically active against Pseudomonas aeruginosa. Among them, MRD C was most active, with MICs of 0.1 to 3.13 μg/ml against many strains of the target organism. Its activity was comparable to that of cefoperazone, ceftazidime and cefsulodin. MRD C-resistant mutants of P. aemginosa appeared spontaneously at a high frequency when cultured in the presence of the antibiotic. No cross-resistance was observed with β-lactam antibiotics. A rapid decrease of turbidity along with spheroplast formation and cell lysis was observed when cells of P. aeruginosa were grown in the presence of MRD C. The compounds exhibited low toxicity and protected mice from experimental infection with P. aeruginosa. The urinary and fecal recoveries of MRD C given subcutaneously were 5 and 18%, respectively.

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A new species of the genus Streptomyces, the proposed name of which is Streptomyces tokashikiensis sp. nov., is described. Soil isolate, strain No. 7124, produces a new antitumor antibiotic FR-900462. The organism is characterized by the presence of spores on the substrate hyphae. Strain No. 7124 is closely related to Streptomyces spiralis in morphological and cultural characteristics, but there are differences in spore surface, growth-permissible temperature, and carbohydrate utilization pattern. Therefore, it was decided to designate strain No. 7124 as a new species within the genus Streptomyces.

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FR-900462 is a new antitumor antibiotic produced by Streptomyces tokashikiensis No. 7124. It was highly active against leukemia P388 and melanoma B16. Furthermore, it has weak antimicrobial activity against some Gram-positive bacteria.

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A new insecticidal antibiotic, aculeximycin (ACM), was produced by an actinomycete identified as Streptosporangium albidum. ACM has been successfully isolated from culture filtrate by a combination of Diaion HP-20, Amberlite CG-50, reversed phase silica gel and Sephadex LH-20 chromatographies. It was found that ACM is a basic glycosidic antibiotic with a molecular weight of 1, 672 including five monosaccharide units, three double bonds and a hemiketal ring by preliminary spectral analyses.
Treatment of ACM with l, 8-diazabicyclo[5, 4, 0]undecene-7 caused a glycosidic bond cleavage to give aculexitriose, pseudoaglycones I and II.

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Treatment of aculeximycin with 2% l, 8-diazabicyclo[5, 4, 0]undecene-7 (DBU) -methanol yielded three products, aculexitriose, pseudoaglycones I and II. The structural elucidation of aculexitriose was carried out by spectral analyses (MS, NMR (¹H-¹H 2D NMR spectroscopy, nuclear Qverhauser effect)) and chemical degradations of aculexitriose and its derivatives. The structure of aculexitriose was established to be a branched trisaccharide, O-6-deoxy-β-D-glucopyranosyl-(l→2)-O-[3-amino-2, 3, 6-trideoxy-β-D-arabino-hexopyranosyl-(l →3)]-6-deoxy-D-glucopyranose. On the other hand the pseudoaglycones I and II were stereoisomers with respect to a chiral center newly formed by the DBU reaction. The pseudoaglycones contain one neutral sugar and one amino sugar, which turned out to be D-mannose and L-vancosamine, respectively.

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Two new nikkomycins were isolated from the fermentation broth of Streptomyces tendae Tü 901/PF 53⁺-3. These new metabolites, nikkomycins pseudo-Z (ψZ, 1) and pseudo-J (ψ-J, 2) differ from the corresponding nikkomycins Z and J by a C-glycosidic bond between C-5 of uracil and C-1' of 5-amino-5-deoxy-D-allo-furanuronic acid instead of an N-lycosidic bond. The structure elucidation was achieved by two-dimensional NMR techniques and mass spectrometry.

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Several carbonate derivatives of hitachimycin have been synthesized and evaluated their activities including antibacterial, cytocidal against HeLa cells and in vivo antitumor against Sarcoma 180. Some of these derivatives showed higher antitumor activity than hitachimycin. Among the derivatives, 11, 15-di-O-methoxycarbonylhitachimycin (2), 11, 15-di-O-ethoxycarbonylhitachimycin (3) and 15-O-methoxycarbonylhitachimycin (9) were most effective in in vivo assay.

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Diazaquinomycin A (1), a new thymidylate (TMP) synthase inhibitor, is poorly soluble in various solvents and exhibits no antitumor activity, while a series of the analogues prepared from 1 are more soluble in water and chloroform than 1, and some of them exhibit antitumor activity in mice. Some analogues in which the lactam rings are replaced by pyridine rings did not inhibit TMP synthase. The diethoxy analogue 25 is a 10-fold more potent inhibitor of TMP synthase than 1. The diacetoxy analogue 23 exhibits significant antitumor activity (T/C: 175%) against Meth-A fibrosarcoma in mice.

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The mutagenic activity in the AMES' Salmonella assay, the antimicrobial activities against bacteria, fungi, and algae, the cytotoxic activities against Ehrlich ascitic tumor cells and L1210 cells, and the phytotoxic activities against Lepidium sativum and Setaria italica, of the unsaturated dialdehyde merulidial and six acetylated, hydroxylated, and cyclopropane ring isomerized derivatives of merulidial, are compared. Some possible structure-activity relationships are discussed.

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The profile of bioconversion products of istamycin (IS) components by a blocked IS mutant of Streptomyces tenjimariensis that lost IS-productivity suggested a possible biosynthetic pathway of IS similar to that of fortimicin (FT) by Micromonospora olivasterospora. Both organisms are resistant to the antibiotics produced by each other. Based on these similarities, they were examined for their capability to convert an FT-intermediate (FT-B) and IS-intermediates (IS-A₀ and -B₀) through their biosynthetic pathways. S. tenjimariensis formed 1-epi-FT-B, 2"-N-formimidoyl-FT-A (=dactimicin) and 1-epidactimicin (a new antibiotic) from FT-B. On the other hand, M. olivasterospora converted IS-A₀ and -B₀ to 2"-N-formimidoyl-IS-A (=IS-A₃) and -B (=IS-B₃), respectively. Thus, the similarity in antibiotic biosynthesis was confirmed between these FT-group antibiotic-producing organisms. It was also found that the major fermentation product of M. olivasterospora is not FT-A (astromicin) but dactimicin.

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Patulolides are a group of 12-membered macrolide antibiotics produced by Penidllium urticae S11R59. An enzyme involved in the conversion of patulolide C to patulolide A was purified from P. urticae S11R59 and characterized. The enzyme showed a single band on SDS-PAGE and molecular sieve HPLC both of which indicated a M_r of 86, 000, indicating that the enzyme is monomeric. However, the enzyme was separated into two bands of very similar pI's (pi 4.2 and 4.3) by isoelectric focusing. Both bands catalyzed the conversion of patulolide C to patulolide A, as demonstrated by activity staining. The two isoenzymes were proved to be oxidases by the simultaneous production of H₂O₂ during the conversion of patulolide C to patulolide A. The molar ratio for patulolides C, A and H₂O₂ was determined to be 1:1:1. The optimum pH and temperature were determined to be 7 and 35-40°C, respectively, and the enzymes were stable at pH 6-9 and 4-40°C. The oxidases showed characteristic absorption at 345 and 450 nm, indicating the presence of flavin as coenzyme. Among several analogues of patulolide C tested, the oxidases showed very narrow substratespecificity; only patulolide C was oxidized to patulolide A. No enzyme activity for the reverse reaction, i.e. from patulolide A to patulolide C, was present in the cell-free extract of P. urticae S11R59. Patulolide C oxidases therefore play a key role in the biosynthesis of patulolides.

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The structures of mercaptan and sodium borohydride reaction products of neocarzinostatin chromophore A (NCS Chrom A) are compared. Implications on the mechanism of activation of NCS are discussed.

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In Streptomyces virginiae, production of virginiamycin is triggered by signal molecules named virginiae butanolide A, B or C (VB-A, B or C: YAMADA, Y. et al. J. Antibiotics 40: 496-504, 1987). We have found a specific VB-C binding protein from S. virginiae, and characterized it by using a tritium-labeled VB-C analogue as a ligand. By equilibrium dialysis in the absence and presence of radio-inert VB-C, a crude extract from 1 g of wet mycelia specifically bound 3.5 pmol of [³H]VB. The binding disappeared after pronase digestion and showed ligand specificity toward cis VB-C (cis VB-C>trans VB-C»A-factor type), indicating that binding was due to a cis VB-C specific binding protein. Scatchard analysis of the binding demonstrated a single class of high affinity binding sites (K_d 1.1 nm) and low number of the binding sites (30-40 sites/genome DNA). By gel filtration on Sephadex G-75 and molecular sieve HPLC, the binding protein was shown to have an M_r of about 20, 000. These results indicate that the substance is a novel VB-C binding protein and suggest that it is a VB-receptor mediating the pleiotropic signal transmitted by VBs in S. virginiae.

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n-Pentyl ether of damavaricin Fc (n-pentyl DvFc) preferentially killed human T-cell lymphotropic virus type I (HTLV-I)-transformed cell lines. The mechanism of action of the drug was investigated using MT-4 cells. Cytotoxic action was diminished by the removal of n-pentyl DvFc from the culture or by the addition of sulfhydryl compounds such as 2-mercaptoethanol and dithiothreitol. The killing activity of n-pentyl DvFc was also diminished by membrane-acting agents including quinidine and diphenylhydantoin. Influx and subsequent efflux of Ca²⁺ were observed when either HTLV-I infected (MT-4 cells) or uninfected cells were treated with n-pentyl DvFc. An efflux of K⁺ was observed in HTLV-I infected MT-4 cells immediately after the exposure of the cells to n-pentyl DvFc. The K⁺ efflux, however, was not observed in the uninfected T cells. n-Pentyl DvFc seems to act primarily on the cell surface of MT-4 cells, leading to the perturbation of membrane function. The restoration of cell growth, however, is critically dependent on the presence of dithiothreitol and 2-mercaptoethanol, implying a role for a free sulfhydryl group in the killing activity.

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Deoxyspergualin has strong immunosuppressive activity in animals. However, it shows less in vitro immunosuppressive activity at the therapeutic concentration used for in vivo administration. Recently, we reported that there are some technical problems with in vitro experiments. In this report, the effects of spergualins were examined under in vitro conditions which excluded these problems, and compared with cyclosporine A (CYA). Spergualins have suppressive effects on mixed lymphocyte response (MLR) and cytotoxic T lymphocyte induction. Furthermore, interleuldn-2 (IL-2) induced proliferation of concanavalin A blasts and CTLL-2 were inhibited at low concentration. However, spergualins have little effect in the early stage of MLR or the mitogen response. These results suggest that spergualins act on the proliferation and differentiation of T cells which respond to growth factors, such as IL-2.

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The in vitro antibacterial spectrum of L-658, 310, a new semisynthetic cephalosporin, was compared with ceftazidime, aztreonam and piperacillin against a wide variety of randomly selected human clinical isolates. The compound was found to be a broad spectrum bactericidal agent that was more potent than any of the comparison drugs against glucose non-fermenting bacteria. It has especially potent activity against Pseudomonas aeruginosa including multiply-resistant strains. The superior activity of L-658, 310 against this group of organisms is attributed to the presence of the dihydroxy substituents on the 2-methylisoindoline moiety of the compound. L-658, 310 is not cross-resistant with either imipenem, ceftazidime or piperacillin (representatives of three different classes of β-lactam compounds) against P. aeruginosa. The lack of cross-resistance with ceftazidime extends to other glucose non-fermenters and several strains of Enterobacteriaceae as well. The compound is active against bacteria known to possess either R-plasmid- or chromosomally-mediated β-lactamases.

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Combinations of L-658, 310 and an aminoglycoside or ciprofloxacin were tested against clinical isolates of Pseudomonas aeruginosa using a checkerboard broth dilution technique. Using the mean fractional bactericidal concentration of ≤0.5 as the criterion for synergy, the combinations L-658, 310/tobramycin and L-658, 310/ciprofloxacin against strains of P. aeruginosa resistant to the companion drug were synergistic. The data plotted as isobolograms showed synergy for all combinations tested. Synergy was clearly demonstrated in time-kill experiments. A greater than 3-log decrease in viable cell count for P. aeruginosa was seen after exposure for 24 hours to subinhibitory concentrations of the combined agents. In in vivo mouse models, the efficacy of L-658, 310 against experimental P. aeruginosa bacteremias was enhanced by the addition of a low dose of an aminoglycoside to the treatment regimen, thus confirming the synergy demonstrated in time-kill experiments.

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The therapeutic activity of L-658, 310 was demonstrated in experimental bacteremias in normal, diabetic and neutropenic mice. Especially potent activity was shown against the usually difficult to control pathogens, Enterobacter cloacae and Pseudomonas aeruginosa, that were resistant to ceftazidime and/or gentamicin. Pharmacokinetic studies in mice showed a linear dose response in serum after the 20 and 50mg/kg subcutaneous dose and urinary recoveries of administered dose of about 60% in 6 hours. Excretion was mainly by glomerular filtration. In a crossover design in rhesus monkeys, the pharmacokinetics of L-658, 310 were similar to those of ceftazidime and suggest a moderately long half-life in serum of humans.

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