Microbial transformation of aklanonic acid, a potential early intermediate in the biosynthesis of anthracyclines.
Sir: Recently, we isolated a new pigment from fermentations of Streptomyces sp. ZIMET 43717". The close structural relationship of this compound (aklanonic acid, Ia, Fig. 1) to anthracyclinones induced us to attempt its biotransformation to anthracyclines by daunorubicin-negative mutants derived from different daunorubicin producing organisms. The results of our experiments provided evidence that aklanonic acid very probably is an early intermediate in the biosynthetic pathway of anthracyclines. Thus, aklanonic acid, its methyl ester, and aklanone, a chemical conversion product of aklanonic acid (Fig. 1)", were fed to fermentations of the mutant strains O3P; and IP,. Both mutant strains were isolated after N-methyl-N'nitro-N'-nitrosoguanidine treatment of daunorubicin-producing Streptomyces griseaus strains. Strain O1P; was derived from IMET JA 5142. Strain IP, is a negative mutant of strain 1P which produces a mixture of new red and blue pigments"'. The chemical structures of the two main red components designated 1P/I and IP/II3) are shown in Fig. 1. Fermentations of the strains O1P; and 1P, were carried out as described2) in 500-m1 flasks each containing 80 ml of medium for 24 hours. Then 3 ml of a solution of substrate in methanol (1 mg/ml) were added to each flask and cultivation continued for 24 hours. Extracts of mycelium with acetone and chloroform (1: 1) were purified by chromatography on KH2PO4 buffered silica gel (chloroform acetone, 10: 2). Identification of the biotransformation products was performed as indicated in Table 1. Glycosides extracted from the culture filtrate were hydrolyzed with 0.1 N HCI. Compound IP/II was purified by column chromatography on silica gel with benzene. The results are listed in Table 1. Aklanonic acid as well as its methyl ester were transformed by mutant O,P, to give e-rhodomycinone, 7deoxy-e-rhodomycinone and glycosides of dauno-
New anthracyclinone metabolites from two blocked mutants of Streptomyces galilaeus MA144-M1.
Two blocked mutants of the aclacinomycin-producing Streptomyces galilaeus MA144-M1 produced new anthraquinones and anthracyclinones. The mutant ANR-58 produced compounds 58A, 58B, 58C (7-deoxy-2-hydroxyaklavinone), 58D (2-hydroxyaklavinone) and 58WR. All these compounds have the 2-hydroxyl group. The mutant ANR-665 produced compounds 665A and 665B. The compounds 58A, 58B and 665A have an anthraquinone skeleton.
Genetics of antibiotic production
INTRODUCTION .............................................................. 596 INCIDENCE OF ANTIBIOTIC PRODUCTION ............ .. ................... 596 General...................................................................... 596 Fungi........................................................................ 597 Actinomycetes ............................................................... 597 Eubacteria .................................................................. 598 GENETIC SYSTEMS AVAILABLE IN ANTIBIOTIC-PRODUCING MICROORGANISMS ............................................................... 598 General..................................................................... 598 Fungi........................................................................ 599 Actinomycetes ............................................................... 601 Transformation in Thermoactinomyces ......... ............................. 601 Conjugation in other genera ................................................ 601 Conjugation and its consequences in Streptomyces ....... .................... 602 Linkage analysis in Streptomyces ........... ................................ 602 Heteroclones in Streptomyces ............ .................................. 604 Heterokaryons in Streptomyces ........... .................................. 604 Plasmids in Streptomyces ............... ................................... 605 Interspecific recombination in Streptomyces ........ ......................... 605 Recombination in N. mediterranei .......... ................................ 605 Recombination in Micromonospora .......... ................................ 605 Recombination by protoplast fusion......................................... 605 Eubacteria.................................................................. 605 SOME REMARKS ON THE PHYSIOLOGY OF ANTIBIOTIC PRODUCTION ... 606 Primary and Secondary Metabolites .......... ................................ 606 Regulation of Secondary Metabolic Pathways .................................. 606 Pleiotropic Effects of Mutations on Antibiotic Production ........ .............. 607 The Adaptive Significance of Antibiotics ................ ...................... 607 "Low Specificity" of Secondary Metabolic Enzymes ........ ................... 607 Chemical Classes of Antibiotics ............................................... 608 Why "Biogenesis"?.................................................. 608 MUTATIONAL STUDIES OF ANTIBIOTIC SYNTHESIS ......... .............. 608 Fungi....................................................................... 608 P. chrysogenum ..................... ............................ 608 A. nidulans ................................................ 610 C. acremonium ................... .............................. 611 P. griseofulvum ..................... ............................ 613 P. patulum ............. .................................... 614 0. mucida ............. .................................... 614 Actinomycetes .................................................. 614 Tetracyclines.............................................................. 614 Macrolides ............. .................................... 615 Aminocyclitols (aminoglycosides)........................................... 615 Novobiocin ............. .................................... 616 Rifamycins .................................................. 616 Actinorhodin ................ ................................. 616 Zorbamycin, etc .................................................. 617 Plasmid involvement in antibiotic synthesis ........... ...................... 617 Eubacteria ........... ...................................... 619 Peptide antibiotics of bacilli ................................................ 619 Butirosin................................................... 619 Nisin.................................................. 619 Prodigiosin .................................................. 620 QUANTITATIVE GENETICS OF ANTIBIOTIC PRODUCTION ...... ........... 620 General Principles of Polygenic Control of Quantitative Characters ..... ....... 620