The growing need of highly potent anticancer agents has stimulated the investigation of streptomycetes producing daunomycin-type anthracyclines. This review compares the features of production strains and their mutants and emphasizes the necessity of application of biochemical and biophysical analytical methods for better understanding these microorganisms and, above all, their further improving and practical usage.

• MeSH
• Biotransformation MeSH
• Daunorubicin biosynthesis   history   MeSH
• History, 20th Century MeSH
• Mutation MeSH
• Antibiotics, Antineoplastic biosynthesis   history   MeSH
• Streptomyces genetics   metabolism   MeSH
• Check Tag
• History, 20th Century MeSH
• Publication type
• Journal Article MeSH
• Historical Article MeSH
• Review MeSH
• Comparative Study MeSH
• Names of Substances
• Daunorubicin MeSH
• Antibiotics, Antineoplastic MeSH

Biosynthesis of anthracyclines in Streptomyces galilaeus during submerged cultivation is considerably influenced by aeration and by the concentration of glucose in the medium. At higher values of oxygen absorption rate both the production of epsilon-pyrromycinone glycosides in the wild strain JA 3043 and its production mutant G-167 and accumulation of free epsilon-pyrromycinone in the blocked mutant G-162 were found to be higher; the production of 7-deoxyaglycones was lower in all strains. The studied strains differed in the rate of glucose consumption and in the ability to utilize starch for the biosynthesis of anthracyclines. A two-fold concentration of glucose in the medium resulted in the G-162 strain in an increase of the yield of epsilon-pyrromycinone by 120%. The production of glycosides in strain G-167 increased even after exhaustion of glucose from the medium and the amount of 7-deoxyaglycones simultaneously decreased.

• MeSH
• Anti-Bacterial Agents biosynthesis   MeSH
• Fermentation MeSH
• Glucose metabolism   MeSH
• Glycosides biosynthesis   MeSH
• Oxygen * MeSH
• Mutation MeSH
• Naphthacenes biosynthesis   MeSH
• Starch metabolism   MeSH
• Streptomyces genetics   metabolism   MeSH
• Carbon metabolism   MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Glucose MeSH
• Glycosides MeSH
• Oxygen * MeSH
• Naphthacenes MeSH
• Starch MeSH
• Carbon MeSH

Cosynthesis of anthracycline compounds was followed in five phenotypic groups of mutants of Streptomyces coeruleorubidus (A--E), blocked in the biosynthesis of the daunomycine complex, and in two mutant types of Streptomyces galilaeus (F, G) blocked in the biosynthesis of glycosides of epsilon-pyrromycinone and aklavinone. Glycosides of daunomycinone and 13-dihydrodaunomycinone were produced in combinations A+B, A+C, A+D, A+E and A+F, epsilon-rhodomycinone was synthesized in combinations A+E, A+F, B+E and B+F. During the cultivation of types B--E with type G or F non-anthracycline compounds, typical of S. galilaeus, were cosynthesized. No cosynthesis could be observed in other combinations of the mutant types. Negative results were also obtained with combinations of mutants of the same group and during cultivation of all mutant types with streptomycetes not producing anthracyclines. A scheme illustrating metabolic pathways leading to the biosynthesis of daunomycinone, aklavinone, epsilon-rhodomycinone in S. coeruleorubidus and S. galilaeus was constructed.

• MeSH
• Daunorubicin analogs & derivatives   biosynthesis   MeSH
• Mutation MeSH
• Streptomyces metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Daunorubicin MeSH

The ability to transorm biologically exogenous daunomycinone, 13-dihydrodaunomycinone, aklavinone, 7-deoxyaklavinone, epsilon-rhodomycinone, epsilon-isorhodomycinone and epsilon-pyrromycinone was studied in submerged cultures of the following strains: wild Streptomyces coeruleorubidus JA 10092 (W1) and its improved variants 39-146 and 84-17 (type P1) producing glycosides of daunomycinone and of 13-dihydrodaunomycinone, together with epsilon-rhodomycinone, 13-dihydrodaunomycinone and 7-deoxy-13-dihydrodaunomycinone; in five mutant types of S. coeruleorubidus (A, B, C, D, E) blocked in the biosynthesis of glycosides and differing in the production of free anthracyclinones; in the wild Streptomyces galilaeus JA 3043 (W2) and its improved variant G-167 (P2) producing glycosides of epsilon-pyrromycinone and of aklavinone together with 7-deoxy and bisanhydro derivatives of both aglycones; in two mutant types S. galilaeus (F and G) blocked in biosynthesis of glycosides and differing in the occurrence of anthracyclinones. The following bioconversions were observed: daunomycinone leads to 13-dihydrodaunomycinone and 7-deoxy-13-dihydrodaunomycinone (all strains); 13-dihydrodaunomycinone leads to 7-deoxy-13-dihydrodaunomycinone (all strains); daunomycinone or 13-dihydrodaunomycinone leads to glycosides of daunomycinone and of 13-dihydrodaunomycinone, identical with metabolites W1 and P1 (type A), or only a single glycoside of daunomycinone (type E); aklavinone leads to epsilon-rhodomycinone (types A and B); aklaviinone leads to 7-deoxyaklavinone and bisanhydroaklavinone (type C); epsilon-rhodomycinone leads to zeta-rhodomycinone (types C, E); epsilon-rhodomycinone leads to glycosides of epsilon-rhodomycinone (types W2, P2); epsilon-isorhodomycinone leads to glycosides of epsilon-isorhodomycinone (types W2, P2); epsilon-pyrromycinone leads to a glycoside of epsilon-pyrromycinone (types W1, P1). 7-Deoxyaklavinone remained intact in all tests. Exogenous daunomycinone suppressed the biosynthesis of its own glycosides in W1 and P1; it simultaneously increased the production of epsilon-rhodomycinone in P1.

• MeSH
• Biotransformation MeSH
• Daunorubicin analogs & derivatives   metabolism   MeSH
• Streptomyces metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Daunorubicin MeSH

Mutants of Streptomyces coeruleorubidus, blocked in the biosynthesis of anthracycline antibiotics of the daunomycine complex, were isolated from the production strains after treatment with UV light, gamma-radiation, nitrous acid, and after natural selection; according to their different biosynthetic activity the mutants were divided into five phenotypic groups. Mutants of two of these groups produced compounds that had not yet been described in Streptomyces coeruleorubidus (aklavinone, 7-deoxyaklavinone, zeta-rhodomycinone and glycosides of epsilon-rhodomycinone). The mutants differed from the parent strains and also mutually in morphological characteristics but no direct correlation between these changes and the biosynthetic activity could be observed in most cases.

• MeSH
• Anthraquinones biosynthesis   MeSH
• Daunorubicin biosynthesis   MeSH
• Glycosides biosynthesis   MeSH
• Mutation MeSH
• Streptomyces cytology   genetics   metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anthraquinones MeSH
• Daunorubicin MeSH
• Glycosides MeSH

A total of 40 substances were tested for their inhibitory effect on the multiplication of a bacteriophage in a growing culture of Bacillus licheniformis and their influence on bacitracin production. Acriflavine was the only substance which, at a concentration of 3 microgram ml-1, completely suppressed phage multiplication while having no effect on the growth of Bacillus licheniformis and on the production of the antibiotic.

• MeSH
• Acriflavine pharmacology   MeSH
• Anti-Bacterial Agents MeSH
• Anti-Infective Agents pharmacology   MeSH
• Bacillus metabolism   MeSH
• Bacitracin biosynthesis   MeSH
• Bacteriophages drug effects   growth & development   MeSH
• Virus Replication drug effects   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acriflavine MeSH
• Anti-Bacterial Agents MeSH
• Anti-Infective Agents MeSH
• Bacitracin MeSH

• MeSH
• Bacteria drug effects   MeSH
• Chemical Phenomena MeSH
• Chemistry MeSH
• Daunorubicin pharmacology   therapeutic use   toxicity   MeSH
• Doxorubicin pharmacology   therapeutic use   MeSH
• Glycosides pharmacology   toxicity   MeSH
• Humans MeSH
• Neoplasms drug therapy   MeSH
• Naphthacenes * pharmacology   toxicity   MeSH
• Nogalamycin pharmacology   therapeutic use   toxicity   MeSH
• Antibiotics, Antineoplastic MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Daunorubicin MeSH
• Doxorubicin MeSH
• Glycosides MeSH
• Naphthacenes * MeSH
• Nogalamycin MeSH
• Antibiotics, Antineoplastic MeSH

Variability in the production of nogalamycin by Streptomyces nogalater var. nogalater was followed in untreated and mutagenized populations of the standard strain NRRL 3035 and its spontaneous variant K-18 using the method of agar blocks with subsequent tests under submerged conditions. In both strains the most active variants were obtained by natural selection without mutagenic treatment; in this way productivity increased by 108% after two selection steps. Treatment with UV-radiation did not yield variants with a highly increased activity. Gamma-radiation extended the variability but, at the same, substantially increased the number of non-producing and low-producing isolates. Relatively high yields of (+)-variants were obtained after treatment with nitrous acid but their activity did not reach that observed in the most active spontaneous variants.

• MeSH
• Bacteriological Techniques MeSH
• Culture Media MeSH
• Naphthacenes biosynthesis   MeSH
• Nogalamycin biosynthesis   isolation & purification   MeSH
• Immersion MeSH
• Streptomyces metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Culture Media MeSH
• Naphthacenes MeSH
• Nogalamycin MeSH

The production of epsilon-pyrromycinone glycosides in Streptomyces galilaeus increased 12-fold, with respect to the wild strain, as a result of a sequential procedure including both natural selection and treatment with mutagens (nitrous acid, UV light and gamma-irradiation). Nitrous acid exhibited the highest mutagenic effect, both in increasing the productivity and in inducing blocked mutants. A mutant strain blocked in the biosynthesis of glycosides and accumulating free epsilon-pyrromycinone as the principal metabolite was obtained.

• MeSH
• Anthraquinones biosynthesis   MeSH
• Glycosides biosynthesis   MeSH
• Nitrous Acid pharmacology   MeSH
• Mutation drug effects   radiation effects   MeSH
• Antibiotics, Antineoplastic biosynthesis   MeSH
• Streptomyces drug effects   genetics   metabolism   radiation effects   MeSH
• Ultraviolet Rays MeSH
• Gamma Rays MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anthraquinones MeSH
• Glycosides MeSH
• Nitrous Acid MeSH
• Antibiotics, Antineoplastic MeSH

Strains of Streptomyces coeruleorubidus ISP 5145, JA 10092 and 39-146, differing mutually in antibiotic activity, were found to produce identical spectrum of metabolites (at least nine antibiotically active glycosides, 13-dihydrodaunomycinone, epsilon-rhodomycinone and a larger number of unidentified compounds); only trace quantities of daunomycin and daunomycinone could be detected. A fraction of glycosides with a higher RF (0.4-0.7), isolated from strain 39-146, could be transformed to daunomycin by mild hydrolysis and to daunomycinone by total hydrolysis. Streptomyces peucetius IMI 101 335 differed from Streptomyces coeruleorubidus in an increased production of epsilon-rhodomycinone and a lower content of glycosides; the zone of daunomycin was most pronounced among the glycoside spots. Streptomyces coeruleorubidus 39-146 exhibited the highest activity in a medium containing 3.5% soluble starch, 3.0% soybean meal, 0.3% NaCl and 0.3% CaCo3; glucose was a more useful carbon source for the remaining strains. The activity of Streptomyces coeruleoribidus was inhibited by 1-propanol, Na-propionate, 5,5-diethylbarbiturate and bacitracin. Ferrous sulphate stimulated the production of glycosides only in strain JA 10092, decreasing simultaneously the production of aglycones.

• MeSH
• Chromatography, Thin Layer MeSH
• Daunorubicin analogs & derivatives   biosynthesis   isolation & purification   MeSH
• Fermentation MeSH
• Glycosides biosynthesis   MeSH
• Culture Media MeSH
• Immersion MeSH
• Streptomyces metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Daunorubicin MeSH
• Glycosides MeSH
• Culture Media MeSH