Two new antibiotics SF2315A and B have been isolated from culture filtrate of an actinomycete strain, Excellospora viridilutea SF2315. They are weakly active against Gram-positive bacteria and inhibited reverse transcriptase of avian myeloblastosis virus. Empirical molecular formula of antibiotics SF2315A and B were determined to be C19H16O5 and C19H20O6, respectively.

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The structures of antibiotics SF2315A and B were determined to be [4aR-(4aβ, 12bβ)] or [4aS-(4aα, 12bα]-4a, 5, 6, 12b-tetrahydro-4a, 8-dihydroxy-3-methylbenz[a]anthracen-1, 7, 12(4H)-trione and [1S-(1β, 4aβ, 6aβ, 12β, 12aα, 12bα)] or [1R-(1α, 4aα, 6aα, 12α, 12aα, 12bα)]-1, 4, 4a, 5, 6, 6a, -12a, 12b-octahydro-1, 4a, 8, 12-tetrahydoxy-3-methyl-6a, 12a-epoxybenz[a]anthracen-7(12H)-one, respectively from their spectroscopic analyses and single crystal X-ray diffraction analyses.

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BMY-28190, an antibiotic complex active against herpes simplex virus type 1 (HSV-1) was produced by the cultured broth of Stmptoalloteichus hindustanus sp. nov., a producing strain of tallysomycins A and B¹⁾. The antibiotic complex was recovered from the broth with Amberlite IRC-50 resin and separated from the coproduced tallysomycins and nebramycins by a series of chromatographies. BMY-28190 exhibited weak inhibitory activity toward Gram-positive and Gram-negative bacteria and strong inhibitory activity toward HSV-1. Structural studies disclosed that BMY-28190 is a move! complex of Υ-poly-D-α, Υ-diammobutyric acids with an average MW of 5, 130.

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A novel aminoglycoside antibiotic, boholmycin, was produced by Streptomyces hygroscopicus H617-25 isolated from a soil sample collected in Bohol Island, the Philippines. It has a pseudotetrasaccharide structure composed of a heptose, two aminosugars and dicarbamoyl-scyllo-inositol. Intrinsic antibacterial activity of boholmycin is weak but it exhibits broad spectrum activity against Gram-positive and Gram-negative bacteria including aminoglycoside-resistant strains. Boholmycin is non-toxic in mice at 1, 000mg/kg intravenously.

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A new antitumor antibiotic BMY-28438 was isolated from the cultured broth of Streptomyces tropolofadens No. K611-97. The antibiotic showed potent cytotoxicity against cultured B16 melanoma cells and remarkable prolongation of life span of mice bearing B16 melanoma. The structure of BMY-28438 was determined as 3, 7-dihydroxytropolone on the basis of spectral analyses and direct comparison with the authentic compound synthesized.

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Neoenactins (NEs) are L-serine-containing antifungal antibiotics produced by Streptoverticillium olivoreticuli. The effect of supplementation of individual amino acids on the production of NEs by this organism was examined from both quantitative and qualitative view points by using a nitrogen source-restricted medium. L-Alanine, L-arginine, L-glutamine, L-histidine, L-lysine and L-proline increased significantly the total productivity of NEs without changing the production ratio of the congeners. The supplementation of L-norvaline, L-isoleucine, L-leucine and L-valine to the culture medium resulted in selective enhancement of the production of NEs A, B₁, B₂, and M₁, respectively, while significant change was not observed in terms of overall production of NEs. When L-norleucine was employed as an amino acid supplement, new NE congeners, named NEs NL₁. and NL₂, were preferentially produced; but the amount of NEs produced was not markedly affected.

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The discovery and biological properties of four novel cholecystokinin antagonists produced by Aspergillus alliaceus is described. One of these was seven times more potent than the previously reported asperlicin.

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Asperlicins B (1, C₃₁H₂₉N₅O₅), C (2, C₂₅H₁₈N₄O₂), D (3, C₂₅H₁₈N₄O₂), and E (4, C₂₅H₁₈N₄O₃) are novel cholecystokinin antagonists produced by Aspergillus alliaceus. The structures of these compounds have been determined by ¹H NMR and MS analysis.

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Feeding of ¹⁴C-labeled amino acids to resting cells of Aspergillus alliaceus strongly supported the intuitive hypothesis that asperlicin is biosynthesized from tryptophan, anthranilate and leucine. The resting cell system was used also to prepare 25 asperlicin analogs via directed biosynthesis in presence of analogs of tryptophan and leucine.

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The reaction of activated derivatives of clavulanic acid with substituted amidoethenyl thiolates to give 9-(2-amidoethenylthio)-9-deoxy derivatives is described; the antibacterial/synergistic and β-lactamase inhibitory activities of the thioethers and their corresponding sulfoxides and sulfones are compared.

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Streptomyces fulvoviridis A933 17M9 1501 is an A933 acylase-defective mutant derived from S. fulvoviridis A933 17M9 and thus produces the OA-6129 group of carbapenems and carbapenams. By further mutation of mutant 1501, 4 types of mutants (OA-6129 A+B1+B2 producers; OA-6129 A+B2 producers; an OA-6129 A producer; non-producers) were obtained. The second type of mutant strains 4N 3607, 5NA 3949-40 and 5NE 252 proved useful for the fermentative production of carbapenem OA-6129 B2. These results of mutagenesis demonstrated that the sequence of carbapenem bioconversion in the horizontal route was hydroxylation at C-8→HSomerization at C-6→sulfation at C-8 hydroxyl.

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Mucor circinelloides f. griseo-cyanus IFO 4563 was found to convert 6-O-methylerythromycin A (TE-031, A-56268) to (14R)-14-hydroxy-6-O-methylerythromycin A ((14R)-14-hydroxy TE-031). The TLC and spectral data of the conversion product were perfectly identical with those of an active major metabolite of TE-031 in humans (M-5).
A related antibiotic, 6-O-methylerythromycin B (TB-010), was able to be similarly transformed to its C-14 hydroxy analogue ((14R)-14-hydroxy-6-O-methylerythromycin B, (14R)-14-hydroxy TB-010).
The MICs of (14R)-14-hydroxy-6-O-methylerythromycin B against some Gram-positive bacteria were almost equal to those of 6-O-methylerythromycin B. It is suggested that the hydroxylation at C-14 of 6-O-methylerythromycms A and B scarcely reduces their in vitro activity.

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A strain of Sebekia benihana NRRL 11111 was found to transform nigericin in three successive steps, giving three compounds which were isolated. Their structure were determined by IR, ¹H and ¹³C NMR, and fast atom bombardment mass spectra.
The first compound resulted from the reduction of the terminal hemiketal ring it was then transformed into the two other compounds as a result of the oxidation of methyl (C-33) into a CH₂OH and COOH group respectively. All these products had lost the ionophoric and antibiotic properties of nigericin and thus were products of a detoxification process

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Specific inhibitors of protein kinase C (PKC) were screened for with a unique detection system, named bleb forming assay. When K562, a human chronic myeloid leukemia cell, was treated with phorbol 12, 13-dibutylate (PDBu) or teleocidin which are activators of PKC, many blebs appeared on the cell surface of K562 within 10 minutes. This appearance of blebs is inhibited by staurosporine and H7 which are known to be PKC inhibitors. Teleocidin and PDBu did not induce bleb formation of HL60, a human acute promyelocytic leukemia cell, and the mouse Friend leukemia cell, even though their morphology was changed 24 hours after treatment with teleocidin or PDBu. Many inducers of terminal differentiation of K562 have the same effect on HL60 and Friend cells. However, the bleb inducing activity of PKC activators seems to be specific for K562. The bleb forming assay satisfied the criteria (simplicity and specificity) required for preliminary screening of activators or inhibitors of PKC.
Teleocidins A and B, and tautomycin (a new antibiotic isolated in our laboratory) were identified as activators of PKC, and also staurosporine and isoflavones (daidzein and genistein) as inhibitors.

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A novel antibiotic tautomycin induced many blebs on the surface of K562 human chronic myeloid leukemia cells, similar to the morphological change induced by phorbol esters. However, tautomycin did not induce nitroblue tetrazolium reducing activity, when HL60 human promyelocytic leukemia cells were caused to differentiate by quinomycin into mature granulocytes. It did not induce spread of HL60 cells, one of the phenotypes of mature macrophages. In addition, it did not compete with phorbol dibutyrate to bind to the cell surface of K562 cells. However, tautomycin significantly activated protein kinase C (PKC) extracted from K562 cells. These results indicate that tautomycin is a new activator of PKC, distinct from phorbol esters.

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Three series of semi-synthetic derivatives of tylosin-related macrolides were evaluated for utility in veterinary medicine. 23-Modified derivatives of 5-O-mycaminosyltylonolide (OMT) possessed potent activity in vitro against species of Pasteurella and Mycoplasma. An experimental infection in chicks caused by Pasteurella multocida was utilized to evaluate efficacy; several of these derivatives of OMT effectively treated the infection when given subcutaneously, but none were effective after oral administration in drinking water. Macrolides retaining the 4'-O-mycarosyl moiety (tylosin, DMT) had relatively poor activity against Pasteurella in vitro. Certain 20-modified derivatives of desmycosin demonstrated good oral bioavailability in chicks and a lead compound with oral efficacy in the Pasteurella infection model was discovered.

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The in vitro and in vivo antimicrobial potencies of KY-109, a pro-drug of KY-087, were compared with those of amoxicillin, cephalexin (CEX), and cefaclor (CCL). The following results were obtained.
KY-087, which is the active form of KY-109, had broad antimicrobial spectrum against Gram-positive and Gram-negative organisms, but showed low antimicrobial activity against Enterobacter sp., Serratia, and Pseudomonas sp. The antimicrobial activities of KY-087 against clinically isolated Gram-positive organisms were superior to those of CEX and CCL. The antimicrobial activities of KY-087 against Gram-negative organisms, such as Enterobacter sp., Serratia, and Pseudomonas sp., were less active. KY-087 showed dose-related bactericidal activity against Staphylococcus aureus and Escherichia coli. The therapeutic efficacy of KY109 against experimental intraperitoneal infections caused by Gram-positive and Gramnegative organisms in mice was comparable to that of CEX but inferior to that of CCL. In experimental granuloma pouch models in rats and kidney infection in rabbits, therapeutic efficacy of KY-109 was either comparable or superior to that of CEX and CCL.

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Ascofuranone demonstrated antitumor activity against FM3A murine mammary carcinoma, implanted in the peritoneal cavity of syngeneic mice, C3H/He. It was more effective by treatment prior to implantation than by that after implantation. Treatment with ascofuranone also increased splenic cytotoxicity and phagocytic activity of host animal cells. Moreover, ascofuranone induced inflammatory cells in the peritoneal cavity which are mainly composed of polymorpho-nuclear leukocytes and macrophages. These cells are more potent in cytotoxicity against FM3A cells than with resident peritoneal cells. The antitumor activity of ascofuranone was suppressed by ip administration of silica, just prior to tumor implantation. These results suggest that the prophylactic antitumor activity of ascofuranone is expressed through the activation of phagocytes.
Ascofuranone also suppressed pulmonary metastasis of B16 melanoma and Lewis lung carcinoma. Treatment after tumor implantaion failed to suppress the metastasis. Single treatment of ascofuranone 4 days prior to implantation decreased the metastasis of Lewis lung carcinoma but not that of B16, whereas single treatment of ascofuranone 24 hours prior to the tumor implantation decreased the metastasis of B16 but not that of Lewis lung carcinoma.

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(14R)-14-Hydroxy-6-O-methylerythromycin A and (14S)-epimer have been isolated as active metabolites from human urine after oral administration of 6-O-methylerythromycin A (TE-031, A-56268). The structures of these metabolites were determined by means of mass, ¹H and ¹³C NMR spectroscopies. Antimicrobial activities of (14R)-14-hydroxy-6-O-methylerythromycin A, a major metabolite, were comparable to those of the parent drug TE-031, whereas (14S)-14-hydroxy-6-O-methylerythromycin A was 4- to 8-fold less active than TE-031 against bacterial standard strains.

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