As reported by Takeuchi, et al.1), kanamycin was adsorbed by phosphoprotein fraction of egg yolk or a similar fraction of ground brain and eluted by acid aqueous methanol or acid water. This modus of adsorption and elution suggests that the mechanism of this adsorption on high molecular acid substances in the tissue such as phosphoproteins is similar to that on cation exchange resin. Kanamycin which has basic groups2) can be adsorbed on high molecular acid substances in the brain by ion exchange mechanism. On the other hand, when water-soluble basic antibiotcs are injected to animals, toxic reaction first appears in eighth nerve system or kidney. Therefore, the authors considered that toxicity of water-soluble basic antibiotics to nerve system or kidney would be related with their basic properties. Then, if a derivative which has not the basic property and retains antimicrobial effect is found, it must have lower toxicity to the nerve system or kidney. From this view point, derivatives of kanamycin were studied.
Kanamycin-di-N-methanesulfonate and kanamycin-tetra- N-methane-sulfonate prepared by S. Umezawa, one of the present authors, were found to retain the bacteriostatic activity. The former had the amphoteric property and the latter the acid. The former had more than 20 times lower toxicity than kanamycin sulfate and the latter about 10 times lower toxicity. Therefore, a similar derivative of fradiomycin (neomycin) was prepared and was found to reduce the toxicity very markedly.
This paper describes bacteriostatic effects, acute toxicities, blood levels and therapeutic effects on bacterial infections of the derivatives above described.
Antibiotics have been displaying their excellent efficacy in the treatment of bacterial infections. More recently it was noticed that some antibiotics would be applicable also to malignant tumors. As a result of a series of screening studies carried out in our laboratory, several antibiotics with antitumor activities were found. They are luteomycin1,2). carzinophilin3,4), mitomycin5,6) and melanomycin7). The author had an opportunity to study the cytomorphological activities of these substances on ascites tumor cells and to compare them with these of known antitumor agents, such as sarkomycin8), nitromin (nitrogen mustard N oxide) 9) and azan M (8-azaguanine methanesulfonic acid-Na) 10).
At present, various transplantable tumors are being employed in various kinds of systems for studies of chemotherapy. For evaluating the antitumor activities, cytomorphological effects of agents on ascites tumor cells would be conceived to have no less important back ground than their effect on inhibition of tumor growth or prolongation of survival of host animals.
The first report of cytomorphological change caused by antitumor substance on ascites tumor was published by Schairer11) and Lettré12) using colchicine. Since discovery of Yoshida sarcoma by Yoshida in 1943, many works with various agents on the tumor have been reported. For instance, colchicine was studied by Satō13), Hirono14) and others; nitromin by Ishidate and Yoshida9,15), Kaise16,17), Tokuyama18) and Ohboshi, et al19,20); sarkomycin by Yamamoto21) and Umezawa, et al.22), and 8-azaguanine by Kondō23), Yamamoto24) and Aizawa25).
In searching the antitumor activity of various substances, the author observed cytomorphological changes of tumor cells and other cellular elements in the ascitic fluid of tumor-bearing animals after administration of the substances mentioned above.
In is an already known fact that α-ketoglutarate is a member of the tricarboxylic acid cycle and it plays a very important role in the carbon metabolism of microorganisms. Lockwood and Stodola1) (1946) found that Pseudomonas fluorescens NRRL No. B-6 produced α-ketoglutarate as major product from glucose under aerobic conditions. Thereafter, several in vestigators have al so reported the production of α-ketoglutarate with various kinds of microorganisms; i.e., in addition to genus Pseudomonas2,3,4,5), genera Escherichia6), Aerobacler6) and Proteus6), Serratia marcescens5,8,9), Bacillus natto7), B. megatherium7), Bact. succinicum7),Gluconoacetobacter cerius10) and Bact. No. 84 C10), Bact. ketoglutarium11), genus Streptomyces12), Mycobacterium butylicum13), Corynebacterium creatinovorans14), Vibrio15), Achromobacter16),Aspergillus niger17), Aspergillus oryzae18,19), Rhizopus18), and Penicillium chrysogenum20,21).
In order to clarify the mechanism of α-ketoglutarate formation by the bacteria, many studies have been carried out. Lockwood et al. 1) reported that glucose oxidation by Pseudomonas fluorescens proceeded to α-ketoglutarate by way of the hypothetical hexose monophosphate shunt reaction sequence. Alternatively, instead of proceeding according to the contemporary hypothesis, it was suggested by Koepsell et al.2,3) that 2-ketogluconate dissimilation might yield a 3-carbon or a 2-carbon fragment in addition to pyruvate, and α-ketoglutarate might arise by condensation of pyruvate with these fragments . Recently, another idea has been shown by Weimberg et al.22) who have investigated the oxidation of L-arabinose by Pseudomonas saccharophila. They found that this pentose could be converted to α-petoglutarate by a series of reactions which did not involve the tricarboxylic acid cycle; i.e., L-arabinose→L-arabono-γ-lactone→L-arabonate→α-ketoglutarate. And other investigators15,23,24,25) reported that α-ketoglutarate would be formed through the tricarboxylic acid cycle. While, Katagiri, Tochikura and Imai6) found that coli-aerogenes bacteria accumulated a large amount of α-ketoglutarate under aerobic conditions such as shaking culture during investigations on the metabolism of glucose. Additional experiments26,27,28,29,30), on the oxidative fermentations of di-and tri-carboxylic acids of the tricarboxylic acid cycle, led to a conclusion that major production of α-ketoglutarate from glucose did not arise by way of the tricarboxylic acid cycle, but occurred by a new “pyrurate-acetate reaction”; i.e., pyrurate+acetyl -CoA→α-ketoglutarate.
Thereupon, investigators often use the inhibitors for the study of biochemical reactions. The potent, specific, and permeant inhibitors of the carbon metabolism would be useful tools for the observation of the relations of the carbon metabolism to cell function. There are numerous reports that the antitubercular substance is available as relatively specific inhibitor of the terminal respiration process. Umbreit and his associates31,32,33) studied the effect of streptomycin on terminal oxidation in Escherichia coli and... Please see PDF for more.
Au cours de nos recherches sur la production d’antibiotiques par Streptomyces, nous avons isolé, à partir d’un prélèvement de terre effectué à Daké, Fukushima Japon, une souche de Streptomyces, que nous avons nommée “Streptomyces No. 1068”, qui s’est montrée douée de propriétés antibiotiques antifongiques particulièrement intéressantes. Les caractéristiques et le procédé qui a donné lieu à l’identification de cette souche seront d’écrites dans d’autres papiers par Mr. M. Arishima.
Nous avons isolé à l’état cristallisé un antibiotique de pentaene, extrait des mycelium cultures subergées, qui inhibit fortement les fongiques pathogènes ou non pathogènes, les champignons levuriformes et les Trichomonas vaginalis. Nous le considérons comme un nouvel antibiotique de pentaene pour ses caractères physiques, chimiques et biologiques et nous l’avons nommé Moldcidine A pour son activité sur moisis.
Taitomycin is a new antibiotic isolated from the mycelium of S. afghaniensis1,2,3). It is highly active against gram-positive bacteria, pathogenic anaerobic bacteria, gram-negative cocci, leptospira and rickettsiae, but not against gram-negative bacilli, acid-fast bacteria, fungi, yeasts, trichomonads, toxoplasma and Ehrlich mouse ascitic tumor. It is the purpose of this paper to describe the therapeutic effect of taitomycin on experimental psittacosis in chick embryo and mouse.
According to Umezawa, et al.1), kanamycin is a basic and water-soluble antibiotic produced by Streptomyces kanamyceticus which was isolated from the soil in Nagano Prefecture in Japan. Kanamycin sulfate used in clinical tests is water-soluble white crystalline powder. It is very stable substance which does not decompose by heating at 100°C for 30 minutes in water solution, and does not change its potency for 1 year at 37°C. The molecular formula of kanamycin sulfate is C18H36N4O11 · H2SO4 · H2O. It was reported that kanamycin is a glucoside consisted of 2 kinds of amino-glucose and desoxystreptamine2). In the kanamycin filtrate, there is a little amount of an effective substance which is separated by paper chromatography. This effective substance includes in its chemical structure an amino-pentose instead of an amino-glucose. This is called kanamycin B. Kanamycin B has antibacterial activity, about one fifth of kanamycin to tubercle bacilli and about 4 times of kanamycin to staphylococci. It shows different side effects, but the products today include too little amount of it to be a trouble.
Kanamycin has wide antibacterial spectrum in vitro, as shown by Umezawa, et al.1,4,5) and Gourevitch, et al.3) It is effective against most of the pathogenic bacteria as Staphylococci, Klebsiella pneumoniae, Diplococcus pneumoniae, Cl. diphtheriae, B. anthracis, E. coli, S. typhi, S. paratyphi, S. dysentheriae, Brucella, etc. (minimum inhibitory concentrations less than 5 mcg/ml, at pH 7. 2) , and also against tubercle bacilli at about 2~5 mcg/ml. However, it is not so effective against some strains of Streptococcus hemolyticus, Proteus and Pseudomonas aeruginosa, is ineffective against Candida and Aspergillus, and also against virus. Kitaoka, et al.6) reported that kanamycin is effective also against Borrelia, Treponema and Leptospira. As for the antibiotic resistance, it is noticeable that, as will be described later, the resistance of E. coli or Staphylococci to kanamycin is acquired very slowly and in low degree. Kanamycin does not show a cross resistance with other known antibiotics.
When kanamycin is injected intramuscularly, it is absorbed rapidly into the blood and found in kidney, liver, lung, spleen, urine and bile considerably in high concentrations, as pointed out by Takeuchi, et al.4) Ichikawa, et al.7) found that kanamycin is excreted in urine in high concentration. As kanamycin is not absorbed when administered orally, it is expected to use for infections of intestines and for preoperative procedure of digestive tracts.
The present authors carried out the clinical experiments mainly on surgical infections. The results are described in this paper.