A new antimicrobial agent, danomycin, has been isolated from fermentation broths of a strain of Streptomyces named Streptomyces albaduncus nov. sp. The antibiotic is a watersoluble, iron-containing polypeptide having activity against Gram-positive bacteria both in vitro and in vivo. The biological and chemical studies revealed that the antibiotic is related to other iron-containing antibiotics such as grisein¹⁾, albomycin²⁾, LA-5352³⁾ or ferrimycin⁴⁾ in that they are water-soluble reddish colored substances having similar patterns of cross resistance.

This paper describes the producing organism, production, isolation and biologiical and physico-chemical properties of danomycin.

Danomycin**, a new antibiotic active against Gram-positive bacteria, especially staphylococci, was isolated from the culture filtrate of Streptomyces albaduncus¹⁾ which is a new strain of streptomycetes. Since the antibiotic was highly active in vivo against experimental infections in mice¹⁾, studies were undertaken on the pharmacology of danomycin prior to clinical investigation. The following toxicological, pharmacological and histopathological studies were therefore made:

I. Acute toxicity

II. Chronic toxicity

A. Effect on the growth of rats

B. Observation of organs at autopsy

C. Microscopic observation

III. Effect on kidney and liver functions

VI. Local action

V. Hematological effects in rabbits

A. Single administration

B. Daily administration

VI. Absorption and excretion

VII. Tissue distribution

VIII. Effect on the cardiovascular system

A. Effect on respiration and blood pressure

B. Effect on the isolated heart of rabbit

C. Effect on peripheral blood vessels

IX. Effect on smooth muscle

A. Effect on the isolated intestine of rabbit

B. Effect on the isolated uterus of rabbit

X. Effect on cholinesterase and monoamine oxidase

Danomycin¹⁾, a product from a strain of Streptomyces albaduncus nov. sp., is a watersoluble antibiotic, orange red in color, and containing iron molecules in its polypeptide structure. Danomycin is effective in vitro against Gram-positive organisms such as Staphylococcus aureus and Pneumococccus, while ineffective against Staphylococcus albus, Streptococcus hemolyticus as well as Gram-negative bacteria.

Because of the high incidence of staphylococcal infections in infancy and young childhood, our concerns have been chiefly about danomycin with its clinical effect on staphylococcal infections. In vitro sensitivities of coagulase-positive staphylococci to danomycin and other several antibiotics, the blood levels and the urinary excretions of danomycin in children, and its clinical effects including the side effects have been studied.

The present report deals with our results obtained.

Blasticidin S, an antibiotic^1,2) shows therapeutic effect on rice blast³⁾, which is economically the most important disease of the rice plants in Japan. The effect is considered to be due to high toxicity of blasticidin S to mycelial growth of Piricularia oryzae, pathogen of the rice blast³⁾. This high toxicity of blasticidin S to mycelial growth seems to be due to a strong inhibition on protein synthesis of Piricularia oryzae⁴⁾. This was indicated by the experiments of Misato et al.⁵⁾ They showed that blasticidin S inhibited ¹⁴C-glutamic acid incorporation into the protein fraction in Piric. oryzae in intact cells, whereas it did not inhibit glycolysis, succinic dehydrogenase activity and oxidative phosphorylation in cell-free extracts of Piric. oryzae and over-all incorporation of inorganic phosphate into nucleic acid fraction in intact mycelia of Piric. oryzae at the minimum growth inhibitory concentration (1 ppm).

The authors found that nitrogen metabolism in the mycelium of Piric. oryzae was remarkably disturbed, when blasticidin S was applied to a culture of log-phase growth. Trichloroacetic acid (5%)-insoluble fraction was decreased, while trichloroacetic acid-soluble fraction and RNA contents were rapidly increased. These results suggest the blasticidin S may exert its primarily fungicidal effect by inhibiting cellular nitrogen metabolism. Protein synthesis in the mycelium might be the primary action site. Therefore this possibility was tested in intact mycelial cells and in a cell-free system.

The present paper is concerned with ¹⁴C-amino acid incorporation into protein fraction in cell-free extracts and intact cells of Piric. oryzae.

Blasticidin S inhibits the growth of Piricularia oryzae at a concentration below 10 ppm. In a previous report¹⁾ it has been shown that 1 ppm of blasticidin S almost completely inhibits the over-all incorporation of ¹⁴C-amino acids into microsomal protein in a cell-free system of Piric. oryzae, whereas it inhibits incompletely the amino acid activating enzymes and the transfer of amino acid to sRNA.

On the other hand, a dose of more than 100 ppm of blasticidins is needed to inhibit the growth of Pellicularia sasakii. Thus, Pellic. sasakii is considered to be non-sensitive fungus to blasticidin S²⁾.

Recently, H. Nakamura (1962)³⁾ found that two isolates of Piric. oryzae increased their tolerance for blasticidin S up to 1,000 ppm and 4,000 ppm respectively, by successive transfers on potato dextrose agar containing increasing concentrations of blasticidin S.

To elucidate the nature of the non-sensitiveness in Pellic. sasakii and tolerance in the adapted clone of Piric. oryzae to blasticidin S, the present study has been carried out.

Recently some attempts have been made to use antibiotics for agricultural use, and several kinds of agricultural antibiotics have already been found. Some of the most improtant agricultural antibiotics in Japan are those against Piricularia oryzae of rice plant, and antipiriculin (antimycin A)¹⁾, blastmycin²⁾, antiblastin³⁾, blasticidins A, B, C⁴⁾ and S⁵⁾ have been reported hitherto. In the authors’ laboratory, antibiotics active on Piricularia oryzae, in vitro and in vivo, have been searched, and blasticidin S has been found to be the most promising anti-blast agent.

Since blasticidin S-producing organisms have been isolated wide from various soil samples, this paper deals with taxonomic studies on five strains of blasticidin S-producing organisms which have been isolated so far in our laboratory.

In Japan, sulfa drugs were introduced for bacillary dysentery in 1941, but became almost ineffective in 1949 as the result of ensuing sulfa-resistant Shigella. Chloramphenicol and chlortetracycline were introduced in 1950 and revealed the therapeutic results comparable to early ones with sulfas. Since then these two antibiotics have been used for bacillary dysentery. With an extensive use of these antibiotics, however, Shigella highly resistant to them have appeared and tended to increase year by year. According to the survey made in major cities in Japan, antibiotic-resistant Shigella were recovered at 5% or so in 1957, 8~10% in 1958, 10~20% in 1959~1960, and 20~30% in 1961. Therefore, how to cope with. the cases infected wiʇh such resistant Shigella raises an urgent question in Japan.

This paper will describe the present status of the Shigella resistant to common antibiotics that were examined in 6 major cities in Japan, Tokyo, Yokohama, Nagoya, Kyoto, Osaka and Kobe, and refer to the chemotherapy of such resistant cases, especially to the kanamycin discovered by Hamao Umezawa.