Alisamycin is a new member of the manumycin group of antibiotics produced by Streptomyces sp. HIL Y-88, 31582, which taxonomically appears to be Streptomyces actuosus. Alisamycin is active against Gram-positive bacteria and fungi, and has a weak antitumour activity.

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Two cytotoxic antibiotics, designated viranamycins A and B, were isolated from the culture broth of Streptomyces sp. CH41. Their structures were elucidated as new 18-membered macrolides related to virustomycin A and concanamycin A from NMR spectral analysis. Viranamycins A and B inhibited the growth of P388 mouse leukemia and KB human squamous-cell-carcinoma cells.

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Dynemicin A, a novel antibiotic containing the bicyclo[7.3.1]-l, 5-diyn-3-ene and 1, 4, 6-trihydroxyanthraquinone functionalities, was isolated from the culture broth of Micromonospora chersina sp. nov. M956-1. The antibiotic exhibited potent in vitro antibacterial and cytotoxic activity, and in in vivo, it cured mice from lethal Staphylococcus aureus infection and prolonged survival time of mice inoculated with murine tumors. Three satellite components, dynemicins L, M and N, were also isolated from the culture broth and chemically characterized.

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Dynemicin A showed extremely potent in vitro cytotoxicity against a variety of murine and human tumor cells. In the experimental animal tumor models implanted ip with P388, L1210 leukemias and B16 melanoma cells, dynemicin A administered ip significantly prolonged life-span of tumor-bearing mice with the wide range of activity. This antibiotic administered iv was also active against iv implanted P388 and L1210 leukemias. In the macromolecule biosynthesis of B16 melanoma cells, dynemicin A inhibited DNA synthesis specifically. The triacetyl derivative exhibited similar in vitro and in vivo antitumor activities to those of the parent antibiotic.

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The dunaimycins are a new complex of spiroketal 24-membered macrolides discovered in the fermentation broth of two actinomycetes. Based on taxonomic studies these two cultures, which were isolated from soil, were identified as Streptomyces diastatochromogenes strains AB 1691Q-321 and AB 1711J-452. The dunaimycins possess both immunosuppressive and antimicrobial activity.

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A novel complex of antifungal and immunosuppressant compounds has been isolated from the fermentation broth and mycelia of two strains of Streptomyces diastatochromogenes. The structures of eight related components were determined employing 1D and 2D homonuclear and heteronuclear NMR spectroscopy and mass spectrometry. These structures represent the first reported spiroketal 24-membered macrolide natural products related to the common 26-membered oligomycins.

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The immunosuppressive effects of the dunaimycins, a new complex of spiroketal 24-membered macrolides, were compared to cyclosporin A, ascomycin, and rapamycin. Each dunaimycin was a potent inhibitor of the mitogenic response observed in mixed murine splenocyte or human leukocyte cultures, and like immunosuppressive drugs these compounds were relatively less potent inhibitors of the constitutive proliferation of murine EL4 thymoma cells. Dunaimycin D4S showed no selectivity in inhibiting the mitogenic response of spleen cells to concanavalin A, pokeweed mitogen, lipopolysaccharide, or phytohemagglutinin. Cyclosporin A and ascomycin did not inhibit interleukin 2 dependent proliferation, whereas the dunaimycins and rapamycin blocked the uptake of [³H]thymidine in mixed cultures supplemented with exogenous interleukin 2. In addition, dunaimycin D4S had no apparent affinity for cyclosporin A or FK-506 immunophilins. Although the dunaimycins inhibited the activity of Na⁺, K⁺ -ATPase, inhibition of this enzyme appeared insufficient to explain the biological activity of these new macrolides. Over a narrow concentration range, dunaimycin D4S showed in vivo immunosuppressive activity in the murine popliteal lymph node hyperplasia model.

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Two endothelin (ET)-binding inhibitors, BE-18257A and BE-18257B, which antagonized ¹²⁵I-ET-1 binding to a porcine aortic smooth muscle membrane, were isolated from the mycelium of a strain of Streptomyces misakiensis. These binding inhibitors were extracted with methanol from mycelium and purified by HPLC.

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The structures of novel endothelin-binding inhibitors, BE-18257A and BE-18257B, were elucidated by spectral analyses and chemical studies. Both inhibitors were found to have a cyclic pentapeptide structure containing three D-form amino acid residues, namely, the structures of BE-18257A and BE-18257B were elucidated to be cyclo(-D-Glu-L-Ala-D-Val-L-Leu-D-Trp-) and cyclo(-D-Glu-L-Ala-allo-D-Ile-L-Leu-D-Trp-), respectively.

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A simple and selective screening method was developed for detecting new aminoglycoside (AMG) antibiotics from actinomycetes strains propagated on solid culture media. The first phase of the screening program is designed to isolate AMG-type activities using: 1) two Serratia marcescens strains, one susceptible and one resistant to AMGs, 2) the high tolerance of AMGs to heat in acidic solutions and 3) the specific resistance of a streptothricin producing strain of Streptomyces lavendulae to streptothricin antibiotics. The second phase of the screening program identifies already known AMG antibiotics through the characteristic spectrum of action which each AMG shows toward a group of bacterial strains synthesizing various AMG-inactivating enzymes.

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A new alkaloid antibiotic tetrazomine was isolated from the culture broth of Saccharothrix mutabilis subsp. chichijimaensis subsp. nov., and its structure was determined to be I by means of spectroscopic measurements. It has an unusual structure which consists of six rings, including piperidine, piperazine, oxazole, and pyrrolidine rings.

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In our study of the structure-activity relationships of cephalosporins bearing quaternary ammonium groups at the 3 position, we postulated that delocalization of the azolium positive charge would lead to an expanded antibacterial spectrum and increased activity. Since quaternization of condensed-heterocyclic compounds such as imidazo[1, 2-a]pyridine gives positive charge delocalization, 7β-[2-(2-aminothiazol-4-yl)-2(Z)-alkoxyiminoacetamido]cephalosporin derivatives (1-53) bearing various (imidazo[1, 2-a]pyridinium-l-yl)methyl moieties at the 3 position were prepared and their antibacterial activity was determined. As expected, these cephalosporins exhibited potent activity against both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa. These results imply that imidazo[1, 2-a]pyridine is a quite useful substituent for improving antibacterial activity and spectrum. The structure-activity studies revealed that a favorable substituent on the imidazo[1, 2-a]pyridine is the cyano radical at the 6 position of the ring, and ethoxyimino or 1-carboxy-l-methylethoxyimino groups are suitable for the alkoxyimino substituent. Among the cephalosporins tested, 7β-[2-(2-aminothiazol-4-yl)-2(Z)-ethoxyiminoacetamido]-3-(6-cyanoimida-zo[1, 2-a]pyridinium-l-yl)methyl-3-cephem-4-carboxylate (45) and 7β-[2-(2-aminothiazol-4-yl)-2(Z)-(l-carboxy-l-methylethoxyiminoacetamido)-3-(6-cyanoimidazo[1, 2-a]pyridinium-l-yl)methyl-3-cephem-4-carboxylate (49) showed good antibacterial activity.

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From our series of studies on cephalosporins bearing condensed-heterocyclic azolium methyl groups at the 3 position in the cephalosporin nucleus, we describe here the synthesis and antibacterial activity of 7β-[2-(2-aminothiazol-4-yl)-2(Z)-alkoxyiminoacetamido]cephalosporins containing imidazo[1, 5-a]pyridinium, imidazo[1, 2-b]pyridazinium, imidazo[1, 2-a]pyrimidinium, imidazo[1, 2-c]pyrimidinium, and pyrazolo[1, 5-a]pyridinium methyl groups at the 3 position. Among the cephalosporins tested, 7β-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(imidazo[1, 5-a]pyridinium-2-yl) (1), (imidazo[1, 2-b]pyridazinium-l-yl) (2), and (pyrazolo[1, 5-a]-pyridinium-1-yl) (3)methyl-3-cephem-4-carboxylates showed potent antibacterial activity and broad antibacterial spectrum. The antibacterial activity of these cephalosporins (1-3) was superior to that of ceftazidime (CAZ). These results imply that the delocalization of the positive charge of the imidazo[1, 5-a]pyridinium, pyrazolo[1, 5-a]pyridinium and imidazo[1, 2-b]pyridazinium groups leads to an expanded antibacterial spectrum and increased activity and that these condensed-heterocyclic compounds as well as imidazo[1, 2-a]pyridine are effective moieties for improving antibacterial activity and spectrum.

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Validamycin A is the major and most active compound among the validamycin complex. Since the site of β-glucosidic attachment to validoxylamine A (1) was expected to affect the activity against the pathogenic fungus, Rhizoctonia solani, all eight possible mono-β-D-glucosides of 1 were prepared. 2-O-, 4-O-, 4'-O-, and 7'-O-β-D-glucopyranosylvalidoxylamine A (2, 4, 6 and 9, respectively) were prepared by microbial β-glycosylation of 1 with strains of Rhodotorula sp. 7-O-and 6'-O-β-D-glucopyranosylvalidoxylamine A (5a and 8a, respectively) were prepared semisynthetically through microbial formation of 7-O-β-D-glucopyranosylvalidamine (10), oxidation of the primary amine of 10 to a ketone, and coupling of the ketone derivative with valienamine, and through microbial formation of 6-O-β-D-glucopyranosylvalienamine (11), and coupling of 11 with (2R)-(2, 4/3, 5)-2, 3, 4-trihydroxy-5-hydroxymethylcyclohexanone (12), respectively. 3-O- and 5'-O-β-D-glucopyranosylvalidoxylamine A (3a and 7a, respectively) were chemically synthesized.

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The biological activities of all eight possible mono-β-D-glucosides of validoxylamine A against Rhizoctonia solani were studied. The attachment of the D-glucosyl residue to validoxylamine A generally diminished the inhibitory activity against trehalase. The introduction of the D-glucosyl residue at the C-3 position did not cause serious loss in activity, while substitution at the C-6' position caused complete loss in trehalase inhibitory activity. Of the eight β-D-glucosides, 4-O-β-D-glucopyranosylvalidoxylamine A (4-O-β-Glc-VA), 3-O-β-Glc-VA and 5'-O-β-Glc-VA exhibited very strong activity against R. solani in the "dendroid-test method". The antagonistic activity of sugars (1 mM) against validoxylamine A and 4-O-β-Glc-VA was examined using the "dendroid-test method". The inhibitory effect of validoxylamine A on hyphal extension was not antagonized by any sugars tested, whereas that of 4-O-β-Glc-VA was antagonized by β-1, 3- and β-1, 4-glucooligosaccharides. Of 2-O-, 3-O-, 4-O- and 7-O-β-Glc-VAs, 7-O-β-Glc-VA exhibiting the lowest activity was not antagonized by any β-glucooligosaccharides tested. The inhibitory effect of 3-O- and 4-O-β-Glc-VAs was antagonized by most β-glucooligosaccharides. The uptake of 4-O-β-Glc-VA into the mycelia was inhibited by laminaribiose and cellobiose but not by maltose.

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A series of new 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(carboxymethoxyimino)acetamido]cephalosporins (1) having various substituted-vinylthio groups at the C-3 position of the cephem nucleus was synthesized and evaluated for antibacterial activity and oral absorption in rats in comparison with cefixime. Of these, the cephalosporins (1a and 1c) with a lower alkoxycarbonylvinylthio group (Z-form) at the C-3 position showed a potent antibacterial activity against Gram-negative bacteria, improved activity against Staphylococcus aureus as well as good oral absorption in rats. The structure-activity relationships of 1 are also presented.

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The gene (aphA-5c) encoding for aminoglycoside-O-phosphoryltransferase (APH(3')-Vc) from Micromonospora chalcea 69-683 was cloned by expression in Streptomyces lividans; it showed strong nucleic and amino acid similarities with previously described streptomycetes aph genes. S1 mapping of the. 5' region indicated that, as with several streptomycete genes, transcription apparently initiates at the translation start codon, with no extragenic ribosome binding site. Comparison of the flanking sequences of the actinomycete aph genes indicates considerable divergence, which is not consistent with the notion that clustered biosynthetic genes for structurally related (or identical) antibiotics are disseminated in their entirety between microbial species.

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The single components of the teicoplanin complex, glycopeptide antibiotics active against Gram-positive bacteria, can be converted in the corresponding de-mannosyl derivatives by cultures of Nocardia orientalis NRRL 2450 or Streptomyces candidus NRRL 3218. Conversely, teicoplanin aglycone and other teicoplanin de-mannosyl derivatives can be converted in the corresponding teicoplanin mannosyl derivatives by cultures of Actinoplanes teichomyceticus ATCC 31121. The biological transformation yields are approximately 40% for de-mannosylation and 90% for mannosylation. The processes allow for the preparation of gram quantities of the de-mannosyl derivatives of teicoplanin and of teicoplanin mannosyl derivatives. De-mannosyl teicoplanin and teicoplanin mannosyl-pseudoaglycone were not amenable to preparation by either acidic or basic chemical hydrolysis.

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