A novel antibiotic complex has been isolated from the fermentation broth of a new species of Actinomadura, A. kijaniata SCC 1256. The complex was separated from the broth by a solvent extraction procedure and consists of 1 major component, designated kijanimicin, and 3 minor components. Kijanimicin was isolated from the complex by column chromatography and/or preparative high pressure liquid chromatography. Structurally the compound is a unique, large acid enol antibiotic and possesses an unusual in vitro spectrum of activity against some Gram-positive and anaerobic microorganisms. In vivo it has also shown interesting activity against malaria.

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Fermentations of Streptomyces violaceoniger TÜ 905 produce the antifungal antibiotics niphithricins A, B, elaiophylin and nigericin. The niphithricins have been characterized as new macrolide antibiotics, and the previously unknown structure of elaiophylin was determined to be a macrodiolide. The niphithricins were biologically active against Gram-positive bacteria and fungi. The mode of action is attributed to an alteration of the membrane permeability.

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( Received for publication June 15, 1981)CC-1065 (NSC 298223) is a potent new antitumor antibiotic with a unique structure produced by Streptomyces zelensis. Improved production, isolation, and assay methods are described along with physico-chemical properties and antitumor activity.

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Thiocillins I, II and III were compared with micrococcin P1 by analysis of acid hydrolyzates of the native and the reduced antibiotics as well as by means of 1H and 13C NMR spectroscopies. As a result of these studies, the differences of these antibiotics were clarified in their structural units, and the structures of thiocillins I. I I and III were assigned on the basis of the proposed structure of micrococcin P1.

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Derivatives of josamycin and isojosamycin modified at C-9 and C-13 have been prepared by reaction sequences involving treatment of josamycin with alcohols, phenol or 1-methyl-1H-tetrazol-5-ylthiol in acidic media. Several tetrahydro derivatives of josamycin and isojosamycin have also been prepared by reaction sequences involving catalytic hydrogenation. From the 1H NMR studies, it was found that the conformation of the macro-lactone portion of 13-O-methylisojosamycin dimethylacetal, a key intermediate, is flexible and changeable with variation of the solvent.

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A new naturally occurring mitomycin, 10-decarbamoyloxy-9-dehydromitomycin B (1), was prepared by treating mitomycin B with sodium hydride. Its analogs having an exo-cyclic double bond in their structure were also synthesized. These compounds showed antibacterial and cytotoxic activities. Among them, 7-amino-l0-decarbamoyloxy-9-dehydro-7-demethoxymitomycin B (2) was the most potent growth inhibitor of KB cells in vitro and, accordingly, it appears to be a potential antitumor agent.

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The 2-methoxypropan-2-yl group fulfills the need of a hydroxyl protecting group generally suitable for the synthesis of β-lactam antibiotics, satisfying the criteria of low-cost, convenience and selectivity in formation, and, above all, ease of deprotection under conditions compatible to the highly sensitive β-lactam function and without contamination of the final products. The use of this protecting group has enabled the successful attachment of 6-[4-(N-acetyl-4-hydroxyl-L-prolylamino)phenyl]-1, 2-dihydro-2-oxo-3-pyridinecarboxyl group, through an amide linkage, to amoxicillin, cephaloglycin, and the 3-[[(1-carboxymethyl)-1-H-tetrazol-5-yl]thio]methyl analogue of the latter, yielding broad-spectrum antibiotics with notably good activities against strains of Pseudomonas aeruginosa.

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Cephalosporin β-lactamase (cephalosporinase; CSase) was purified from a strain of Pseudomonas aeruginosa resistant to β-lactam antibiotics. The purified enzyme preparation gave a single protein band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and its molecular weight was about 34, 000. The specific activity was 49.7 μmoles/minute/mg of protein of the purified enzyme for the hydrolysis of cephaloridine. The optimal pH and optimal temperature were about 8.0 and 40°C, respectively. Its isoelectric point was 8.7. The enzyme activity was inhibited by iodine, some divalent ions, and some semisynthetic β-lactam antibiotics, including cephamycin derivatives such as moxalactam and YM09330. Mouse antiserum obtained against the purified enzyme showed no cross-reaction with other types of β-lactamase in neutralization test.

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Streptomyces refuineus, the microorganism which produces the DNA reactive antibiotic anthramycin, has been shown to possess a quite specific mechanism to survive and grow in the presence of this antibiotic. Stationary phase cells are insensitive to anthramycin since the antibiotic is prevented from entering these cells. However, cells in early log phase are inhibited by concentrations of anthramycin that are later produced by these same cells. Significantly, sibiromycin, a closely related antibiotic, is taken up by cells of S. refuineus independent of the age of the culture. Anthramycin reacts in vitro equally as well with DNA isolated from S. refuineus and other procaryotic and eucaryotic cells. When S. refuineus has reached the production phase the anthramycin is probably biosynthesized outside the cell membrane which also becomes specifically impermeable to anthramycin.

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Streptomyces kanamyceticus ISP5500, S. fradiae ISP5063 and S. griseus ISP5236, which produce kanamycin, neomycin or streptomycin respectively, were highly resistant to the antibiotics they produced. Polyphenylalanine synthesis in cell free systems was also resistant to the action of the antibiotics. Reciprocal exchange between ribosomes and 5150 fractions from the three strains revealed that the S150 fraction of each strain had an enzyme activity that inactivated the appropriate antibiotic whereas the ribosomes were susceptible to the antibiotics. It was concluded that the resistance of the in vitro polyphenylalanine synthesizing systems of these antibiotics was due to the presence of inactivating enzymes. Furthermore, S. fradiae and S. kanamyceticus were highly resistant to aminocyclitol-containing aminoglycoside antibiotics other than those produced by the two strains. In these cases, the inactivating enzymes were found to have a major role in the resistance mechanism. However, the resistance of S. kanamyceticus ISP5500 to streptomycin seems to be due to resistance at the ribosomal level.

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The influence of streptomycin (SM) on protein synthesis in a SM-producing strain was investigated using polyuridylic acid-directed polyphenylalanine synthesis in cell-free extracts. Tolerance of protein synthesis to SM developed with increasing culture age of cells and could be attributed to a decrease in affinity of the ribosomes for SM and an increase in SM 6-kinase activity in the cells. SM 6-phosphate produced from SM by SM 6-kinase did not bind to ribosomes and, furthermore, ribosome-bound SM was effectively released on phosphorylation with SM 6-kinase. Also a decrease in cell permeability to SM during the production phase may contribute in protecting protein synthesis from the antibiotic.

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An ion pair reversed phase HPLC method for the determination of clavulanic acid has been developed. Since clavulanic acid had poor absorption (λmax 201 nm in water) in a UV-region suitable for HPLC detection, the detectability was enhanced by bathochromic shift of λmax due to solvent effect. The shifts of λmax, were measured with the solutions containing clavulanic acid, tetrabutylammonium bromide, and phosphate buffer salts in aqueous methanol. The magnitudes of the observed shifts were investigated with respect to pH, ionic strength, methanol content, and TBAB concentration. The results indicated that TBAB concentration was the predominant factor responsible for the bathochromic shifts. Taking account of the results together with solvent effects on the retention of clavulanic acid on hydrophobic stationary phase, HPLC condition suitable for detection and separation of clavulanic acid in urine was established as follows; mobile phase: 10 mm TBAB+0.6 mM NaH2PO4+0.4 mM Na2HPO4 in H2O-MeOH, 10:1 (v/v) (pH 7.02), flow rate: 1.5 ml/minute, stationary phase: LiChrosorb RP-18 (25 cm×4.6 mm i.d.), detection: UV 220nM. The applicability of the present method is demonstrated by determining the time course of urinary excretion of clavulanic acid after oral administration of a conjugated tablet of clavulanic acid and amoxicillin to human subject.

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We have developed a competitive enzyme immunoassay (EIA) using co-polymer of styrene and maleate as the solid phase and glutaraldehyde for binding of the antibody to the solid phase. This assay showed a striking efficacy in its use for the assay of tobramycin (TOB). Furthermore, the pharmacokinetics of TOB were studied in six healthy male volunteers after the administration of 60- or 90-mg doses intramuscularly.

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Activities of marker enzymes for various cell components were studied with extracts of adriamycin-, aclacinomycin A- and bleomycin-resistant cells and with partially purified plasma membrane fraction of aclacinomycin A-resistant cells, in comparison with those of the parental cells. Alkaline phosphodiesterase and Na+-K+-ATPase activities were observed to alter in the drug-resistant sublines, but other enzymes showed similar activities in the resistant cells to those in the parental cells. Alkaline phosphodiesterase activities in all the resistant sublines were higher than that in the parental cells. Na+-K+-ATPase activities of anthracycline-resistant sublines were lower and that in bleomycin-resistant cell line was higher than that of the parental cells. The adriamycin-resistant cells exhibited the same level of alkaline phosphodiesterase activity with the aclacinomycin A-resistant cells: υmax was the same with, and the affinity was twice stronger than the parental cells. The bleomycin-resistant cells showed ca. 30% υmax in comparison with the sensitive cells, and 17 fold higher affinity than the parental cells. The current results, concerning changes of membrane-associated enzymes in drug-resistant sublines of L5178Y cells, support the assumption that the resistance is due to alteration of plasma membrane transport systems.

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Bestatin, a chemically defined immunostimulant of low molecular weight, suppressed the gradually-occurring lymph node metastasis of P388 leukemia in CDF1 mice when administered i.p. at the doses of 1- 30μg/mouse. It could not, however, suppress the established large metastasis of P388 leukemia. Lymph node cells isolated from the mice given bestatin i.p. at 1 and 30μg/mouse showed stronger cytostatic activity against P388 leukemic cells in vitro than those from the untreated mice.

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