Novel antibacterial antibiotics napyradiomycins A, A1, B2, B3, C1 and C2 have been isolated from the culture broth of Chainia rubra MGS02-AFI. In this paper, taxonomy of the producer, and production, isolation, physico-chemical properties and biological activities of napyradiomycins are reported. They contain the naphtopyran chromophore and halogens, and inhibit the growth of Gram-positive bacteria including drug-resistant strains.

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Structures of novel antibiotics, napyradiomycins A, B1, B2, B3, C1 and C2 were determined. By X-ray crystallography, napyradiomycin B2 was determined to be (3R, 10aR)-3-chloro-10a-[[(1 R, 3S)-3-chloro-2, 2-dimethyl-6-methylenecyclohexyl]methyl]-3, 10a-dihydro-6, 8-dihydroxy-2, 2-dimethyl-2H-naphtho[2, 3-b]pyran-5, 10-dione. The structures of other napyradiomycins were elucidated by NMR studies. Napyradiomycins C1 and C2 have unique structures which contain 14-membered ring cyclized by carbon-carbon bond.

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Fermentation of Streptomyces aminophilus subsp. notonesogenes 647-AV1 produced a mixture of antifungal antibiotics. Notonesomycin A, the main component has been characterized as a new macrolide antibiotic containing a sulfate group, a malonate moiety, two deoxysugars and a 1, 3, 4-trisubstituted benzene system in the molecule. It was active against some fungi and Gram-positive bacteria in vitro and effective against the sheath blight disease of rice plant in a green house test.

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In a selective screening for antifungal metabolites, six new clavam antibiotics, clavamycins A, B, C, D, E and F, have been detected from two variants of Streptomyces hygroscopicus NRRL 15846 and NRRL 15879.

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Clavamycins A, B, C, D, E and F represent new members of the clavam antibiotics group. Their purification was achieved by a variety of preparative chromatographic methods, essentially on reversed phase carrier. The structures were deduced from spectroscopic properties, especially from extensive NMR studies.

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2-Heterocyclylmercaptoalkyl penems were synthesized and their in vitro potency was established. The compounds exhibit moderate to strong antibacterial activity against various Gram-positive and Gram-negative bacteria. Their antimicrobial activity is related to the nature of the heterocycle, the length of the hydrocarbon spacer between the 2-position of the penem nucleus and the mercapto group, and the substitution pattern of the C-6 position of the penem skeleton.

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The unstability of neocarzinostatin (NCS), apo-NCS and NCS-chromophore (NCS-chr) has been investigated by using an extra-weak chemiluminescence (CL) analyzer. A significantly high emission intensity (10, 840 counts/10 seconds) was detected from NCS under dark conditions at 20°C, while no significant emission was observed in other antitumor antibiotics, such as, mitomycin C and pepleomycin. This high emission intensity of NCS was due to NCS-chr I (epoxide form) but not apo-NCS. The functional group generating the high extra-weak CL of NCS-chr I is probably the epoxide in the molecule, since the emission intensity of NCS-chr I (epoxide form) is much higher than that of NCS-chr II (hydrochloride adduct form). The extra-weak CL emission of NCS decreased under a nitrogen atmosphere and it was greatly enhanced under an oxygen atmosphere. The spectral analysis of NCS showed emission peaks around 460 and 570 nm. These observations strongly suggest that one of the emission species of NCS-chr may be due to singlet oxygen.

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The biosynthesis of the avermectins, a group of 16 membered macrolides with potent anthelmintic and insecticidal activity produced by Streptomyces avermitilis, was studied by supplying cultures with ¹⁴C and ¹³C precursors. [1-¹⁴C] and [2-¹⁴C]acetate and propionate were poor precursors of the avermectins and were instead rapidly oxidized to ¹⁴CO₂. The S-methyl of methionine in contrast was incorporated extensively and equally into the three methoxyl groups of the avermectins. The carbon backbone of methionine was not a precursor of the avermectins. Feeding of [1-¹³C]glucose yielded avermectins labeled specifically in the C1' and C1" of the oleandrose moiety and in the aglycone moiety in carbons known to be derived from the methyl of acetate. Feeding [U-¹³C]glucose showed that the entire avermectin molecule is derived from glucose carbons.

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Though all the streptonigrin derivatives with modifications in the carboxyl group on C2' were active as electron acceptors in the oxidation of NADH by Clostridium kluyveri diaphorase as well as streptonigrin, the glycine derivative did not show any marked effect on the KCN-insensitive oxidation of glutamate by rat liver mitochondria, suggesting a poor membrane transport of the glycine derivative. Sakyomicin A also induced the KCN-insensitive oxidation of glutamate by mitochondria, while a trace activity was observed by mitomycin C and the effect of doxorubicin was negligible. Like streptonigrin, the autoxidation of a reduced form (hydroquinone) of sakyomicin A to a quinone accompanied the generation of H₂O₂. However, exogenous NADH was oxidized by mitochondria in the presence of sakyomicin A but not streptonigrin.

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The naphthoquinone moiety was proven to be essential to the biological activities of sakyomicin A using various naphthoquinone derivatives. Among the naphthoquinones tested, juglone (5-hydroxy-1, 4-naphthoquinone) which resembles the partial structure of sakyomicin A was the most active in cytotoxicity against murine lymphosarcoma L5178Y cells, electron acceptor function in the oxidation of NADH by Clostridium kluyveri diaphorase or rat liver mitochondria and inhibition against avian myeloblastosis virus reverse transcriptase. The significantly lower cytotoxicity of sakyomicin A as compared with juglone was attributable to its poor membrane transport. The inhibition of reverse transcriptase activity may result from the interaction between a sulfhydryl group in the active center of the enzyme and quinone groups of the naphthoquinones and sakyomicin A.

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Forphenicinol, S-2-(3-hydroxy-4-hydroxymethylphenyl)glycine, prolonged the survival period of mice implanted with Meth A fibrosarcoma or Lewis lung carcinoma. The effect was observed in the mice when the primary tumor was removed by amputation. At autopsy, metastasized tumors were found in all dead mice but no tumor foci were detected in any of the mice still alive at the time of sacrifice. Moreover, forphenicinol suppressed the growth of subcutaneously implanted adenocarcinoma 755. When combined with surgical resection of primary tumors, forphenicinol administration both before and after resection suppressed the growth of recurrent tumors and prolonged the survival period of the mice.

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Forphenicinol stimulated the production of BCG-induced γ-interferon in BCG-sensitized mice as much as 11-fold whereas it did not induce interferon production in unsensitized mice. This stimulatory effect was also observed in mice immuno-suppressed by cyclophosphamide. Furthermore, BCG-induced γ-interferon production was reduced in mice by treatment with an anti-macrophage agent (silica gel), and forphenicinol administration into such mice could augment their interferon production. Transplantation of macrophages from forphenicinol-treated mice into mice injected with silica gel remarkably enhanced the BCG-induced interferon production in the recipients. These results suggest that the stimulatory effect of forphenicinol on BCG-induced γ-interferon production in mice was due to the activation of macrophages.

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Oral administration of forphenicinol, S-2-(3-hydroxy-4- hydroxymethylphenyl)glycine, increased the production of la-positive peritoneal macrophages in healthy mice. Moreover, forphenicinol increased la-positive macrophages in L1210-bearing mice. Though forphenicinol was ineffective against mouse leukemia L1210 when administered alone, in combination with L1210 vaccine it prolonged the survival time of 1, 1210-bearing mice and the increase in the number of la-positive macrophages in peritoneal cavity coincided with the prolongation of the survival time. These results suggest that the initial action of forphenicinol is the preferential induction of la-positive macrophages, which play a role in the subsequent activation of various immune responses including macrophage activation.

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Cells of Aspergillus niger normally release not all but of some specific cell constituents viz., lysine, proline, ATP, P₁, Na⁺, K⁺ and Ca²⁺ in the absence of mycobacillin. Mycobacillin enhances the release of these materials without causing lysis. The time and concentration of mycobacillin for optimum release depends on the nature of the materials involved.

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Streptoverticillium hadanonense KY11449 was found to produce a 12-lipoxygenase inhibitor MY3-469. The compound was purified by chromatography on Diaion HP-10, charcoal, Sephadex LH-20 and crystallization. The chemical structure of MY3-469 was determined to be 3-methoxytropolone on the basis of its physico-chemical properties. The half maximal inhibitory concentration (IC₅₀) of MY3-469 against bovine platelet 12-lipoxygenase was 1.8×10^-6 M. The compound did not inhibit bovine platelet cyclooxygenase at 10^-3 M and showed weak inhibition (IC₅₀ 2.8×10^-4) against 5-lipoxygenase of rat basophilic leukemia cells. The results indicate that MY3-469 is a potent and selective inhibitor of 12-lipoxygenase.

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Analysis of gilvocarcin V production by Streptomyces arenae in complex and chemically defined media revealed strong nitrogen repression of antibiotic biosynthesis. Nitrogen regulation was first suggested by the observation of a 10-fold increase in gilvocarcin V production when the ammonium ion trapping agent Mg₃(PO₄)₂•8 H₂O was added to complex medium. In a chemically defined medium, cell mass increased as the initial ammonium sulfate concentrations approached 7.5 mM; however, antibiotic production was strongly repressed at ammonium sulfate concentrations exceeding 1.5 mm. Repression of gilvocarcin V production at 7.5 mM ammonium sulfate was maximally reversed by adding Mg₃(PO₄)₂•8H₂O to the medium at 25 mM; specific antibiotic production attained a level 2.5-fold higher than at the nonrepressive ammonium salt concentration of 1.5 trim. Evaluation of the effects of soluble inorganic phosphate concentrations upon gilvocarcin V titers suggested that the relatively insoluble Mg₃(PO₄)2•8 H₂O must in fact serve as an ammonium ion-trapping agent, as previously reported in other fermentation systems, not as a supplementary source of phosphate for growth and antibiotic production. These studies also revealed a minor repression of antibiotic synthesis at elevated levels of soluble phosphate. Comparisons of several amino acids as nitrogen sources in a Mg₃(PO₄)₂•8 H₂O-containing medium indicated that L-aspartic acid and glycine promoted the highest yields of gilvocarcin V. Metabolism of these two amino acids into precursors of the polyketide pathway for gilvocarcin V biosynthesis is postulated.

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