Production of new anthracycline antibiotics 1-hydroxy-oxaunomycin and 6-deoxyoxaunomycin by limited biosynthetic conversion using a daunorubicin-negative mutant.

A limited biosynthetic conversion of some known anthracyclinones using a specific daunorubicin-nonproducing mutant provided four new anthracycline antibiotics: 1-Hydroxy-10-methoxycarbonyl-13-deoxocarminomycin; 1-hydroxy-13-deoxocarminomycin; 1-hydroxyoxaunomycin and 6-deoxyoxaunomycin. Their isolation and purification from bioconversion broth, structural determination and antitumor activities against leukemic L1210 cells are described.

[Actinomadura species as antibiotic producers]. / Vidy roda Actinomadura kak produtsenty antibiotikov.

Screening of antibiotic-producing cultures among Actinomadura showed that definite species mainly produced antibiotics of the same groups. Thus, carminomycins were produced by all the 4 studied strains of A. carminata, maduramycins were produced by 3 strains of A. rubra, prodigiozines were produced by 3 strains of A. madurae and luzopeptines were produced by 6 strains of A. recticatena. Supposedly, new antibiotics with original spectral characteristics were isolated from 2 strains of A. fulvescens. There was a clear-cut relation of the number of the active strains and their antibiotic productivity in definite media to their species. The liquid nutrient media, such as yeast-sucrose, soya-glucose and soya-glucose with cobalt chloride proved to be the most efficient in the primary screening of antibiotic-producing cultures.

Microbial conversion of anthracyclinones to carminomycins by a blocked mutant of Actinomadura roseoviolacea.

New anthracycline antibiotics, 1-hydroxy-11-deoxycarminomycin II and 11-deoxycarminomycin II were produced by a blocked mutant MuW1 of Actinomadura roseoviolacea from epsilon-pyrromycinone and aklavinone, respectively. We found that the enzyme catalyzing hydroxylation at the C-11 position was not lost but was down regulated in the strain MuW1.

[Teichoic acid from the cell wall of Actinomadura carminata--a producer of the antibiotic carminomycin]. / Teikhoevaia kislota kletochnoi stenki Actinomadura carminata-- produtsenta antibiotika karminomitsina.

The cell walls of Actinomadura carminata, producing the antibiotic carminomycin, contain a poly(glycerol phosphate) teichoic acid. The polymer belongs to 1,3-type and consists of about 8 glycerol phosphate units, two of them have 2-acetamido-2-deoxy-alpha-D-galactopyranosyl substituent and one--3-O-methyl-beta-D-galactopyranosyl-(1----3)-2- acetamido-2-deoxy-alpha-D-galactopyranosyl residue at C2 of glycerol. The structure of the polymer was established by chemical analysis and 13C-NMR spectroscopy. The teichoic acid accounted for about 10% of the cell wall dry weight. 3-O-methylgalactose in the structure of the teichoic acid was found for the first time.

13-Deoxycarminomycin, a new biosynthetic anthracycline.

A new antitumor antibiotic, 13-deoxycarminomycin, has been isolated from the anthracycline complex produced by Streptomyces peucetius var. carminatus (ATCC 31502), a biochemical mutant of Streptomyces peucetius var. caesius, the doxorubicin-producing microorganism. The new anthracycline, showing antibacterial and cytotoxic activity in vitro, was found active against P-388 murine leukemia.

[Selection of active strains of Actinomadura carminata, the producer of carminomycin]. / Selektsiia aktivnykh shtammov Actinomadura carcminata--produtsenta karminomitsina.

The method of selecting active strains among a definite group of analogue-resistant mutants was used on the basis of studying the dependence of the carminomycin-producing organism growth and the antibiotic synthesis level on some metabolites. As a result, gamma-ray induced mutants 4 times more active than the parent strains were obtained.

[Effect of the pH of the medium on the growth of a carminomycin producer and on the biosynthesis of the carminomycin complex]. / Vliianie pH sredy na rost produtsenta karminomitsina i biosintez karminomitsinovogo kompleksa

The effect of the nutrient medium acidity on the growth of the carminomycin-producing organism and formation of the carminomycin complex with its aid was studied. Satisfactory development of the organism was observed when pH of the nutrient medium on the culture inoculation was 4.9 to 8.5. A shift in the alkaline and acid values of pH to 6.3--6.4 was registered during the first 24 hours of the culture growth. The biosynthesis of carminomycin depended on the culture growth time and pH value of the nutrient medium and culture fluid during the fermentation process. Maximum production of the carminomycin complex and its active components was observed on the 7th--8th day of the culture growth. The medium reaction close to the neutral one was optimal for biosynthesis of the carminomycin complex and its active components. Under acid, as well as alkaline conditions the antibiotic production was markedly lower.

[Relationship between the quality of the inoculum material and carminomycin biosynthesis by a culture of Actinomadura carminata]. / Zavisimost' biosinteza karminomitsina kul'turoi Actinomadura carminata ot kachestva posevnogo materiala.

The effect of the inoculum mycelium quality on carminomycin biosynthesis by Actinomadura carminata was studied. The time of the organism growth on the culture medium containing cornsteep liquor continued for 6 hours without losing by the inoculum of its seeding qualities during that period. The mycelium growth in the inoculum was more intensive under conditions of moderate aeration, i.e. 0.98-2.64 mg O2H1-min. Anincrease in the aeration rate up to 18.56 mg O2/1-min resulted in the growth suppression up to 40 per cent. No correlation between the aeration rate during the inoculum growth and the culture capacity for carminomycin biosynthesis and of the content of the complex in active components the fermentation medium were observed, when a 5-10 per cent of inoculum was used.

[Effect of aeration conditions on the biosynthesis of carminomycin by an actinomadura carminata culture]. / Vliianie uslovii aératsii na biosintez karminomitsina kul'turoi Actinomadura carminata

The effect of the aeration rate on biosynthesis of carminomycin by Actinomadura carminata and biochemical changes in the fermentation broth on the use of 3 complex media of different composition was studied. The carminomycin-producing organism can grow and produce the antibiotic within the ranges of the aeration changes from 0.98 to 18.56 mgO2/1-min. A decrease in the maximum rate of oxygen dissolution up to 0.98 mgO2/1-min resulted in some decrease in the activity level. Intensive aeration, i.e. 18.56 mgO2/1-min induced suppression of the antibiotic production by 25 per cent.

[Subsequent mutagenesis under the action of UV rays in a culture of Actinomadura carminata, a producer of carminomycin]. / Posledovatel'nyi mutagenez pod deistviem UF-luchei v kul'ture Actinomadura carminata produtsenta karminomitsina

The succession of some markers on the chromosomes of Actinomadura carminata was shown with the method of successive mutagenesis based on the preferable effect of the mutagen on DNA in the site of replication. The spore germination was synchronized by selection of the spores of the definite size and maintenance at a temperature of 0 degrees. The periods of formation of the highest numbers of morphological and auxotrophic mutants were compared with the time of DNA replication.

[New producer of carminomycin, Actinomycer cremeospinus sp. nov]. / Novyi produtsent karminomitsina--Actinomyces cremeospinus sp. nov.

An actinomycete strain No. 85 was isolated from a soil sample on media with bleomycin. It was described as a representative of a new species. Actinomyces cremeospinus sp. nov. An antibiotic substance identical with carminomycin, an antitumor antibiotic was isolated from the culture fluid of the strain.

[Optimization of the nutrient medium makeup for the biosynthesis of carminomycin using mathematical methods of experimental design]. / Optimizatsiia sostava pitatel'noi sredy dlia biosinteza karminomitsina s pomoshch'iu matematicheskikh metodov planirovaniia éksperimenta

The nutrient medium for biosynthesis of carminomycin by Actinomadura carminata, strain 4281 was optimized with the methods of mathematical planning of the experiment. The starting variant of the medium, production of carminomycin on which was assumed equal to 100 per cent was enriched during the experiments carried out according to the patterns of the orthogonal latin squares. The production levels of carminomycin on the above medium was more than 3 times higher than those on the starting medium.