A new arginine antimetabolite was isolated from the fermentation broth of a new strain of Streptomyces and identified as 2-methyl-L-arginine.

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5-(3-Azidopropyl)-5-methyl-2, 4-imidazolidinedione was prepared either from 5-(3-chloropropyl)-5-methyl-2, 4-imidazolidinedione or 5-methyl-5-{3-[(4-methylphenyl)sulfonyloxy]-propyl}-2, 4-imidazolidinedione and hydrogenolyzed to the corresponding amine which, after carbamimidoylation, afforded 2-methyl-DL-arginine upon acid hydrolysis. Racemic 2-methylarginine was converted enzymically to a mixture of 2-methyl-D-arginine and 2-methyl-L-ornithine. 2-Methyl-L-arginine was reconstructed from 2-methyl-L-ornithine via its Cu(II) chelate with O-methyl-isourea and 2-methyl-D-ornithine was obtained by alkaline hydrolysis of 2-methyl-D-arginine.

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Enterocin is a new antibiotic isolated from cultures of two strains of Streptomyces, which were given the names Streptomyces candidus var. enterostaticus WS-8096 and variant M-127 of Streptomyces viridochromogenes¹⁾. Its elementary analysis and mass spectroscopic measurement suggest the molecular formula is C₇₂H₂₀O₁₀. The ultraviolet absorption gave two maximal peaks at 250 nm and 283 nm in methanol. Enterocin has static activities against gram-positive and gram-negative bacteria and no activity against fungi and yeast.

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Two antibiotics isolated from a culture MA-2465 were identified as aureothin and labilomycin, the chemical structures of which had been reported previously. It was also concluded that mycolutein and pulvomycin isolated as antibiotics in 1955 and 1957 respectively are also identical with aureothin and labilomycin. A cursory study of MA-2465 indicates that it is distinctly different from the culture which was first observed to produce labilomycin and is probably different from the organism first noted to produce aureothin.

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Strain S15-1 which produces antiviral antibiotic S15-1 belonging to the streptothricin group of antibiotics was isolated from a soil sample. Cell analysis, colony morphology, the absence of sporangia-like vesicles, the formation of spores in chains of the Rectus Flexibilis type, and the ability to produce melanoid pigment, indicate that this strain belongs to the genus Streptomyces WAKSMAN and HENRICI. A comparison of the characteristics of strain S15-1 with related Streptomyces show that it should be identified as Streptomyces purpeofuscusYAMAGUCHI and SABURI. The investigation of cultural conditions show that soluble starch and meat extract are the most suitable carbon and organic nitrogen sources for the production of antibiotic S15-1. Strain S15-1 grew poorly on media with no organic nitrogen sources, and did not produce the antibiotic. Antiviral antibiotic S15-1 is accumulated at the highest level after 3 or 4 days growth of the producing organism.

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Increase in antimycin A production was achieved through a parallel strain and medium improvement program: a 125-fold augmentation (75 to 9, 500μg/ml) was
obtained. The selective system included antimycin A productivity, conidiation, sensitivity to ultraviolet radiation, growth rate and yield, and absence of pigment and actinomycin D production. Among the original strains tested one natural isolate possessed high productivity and several of the above characteristics, and was selected for mutagenesis . Spontaneous and induced variability was then exploited in isolating high-producing strains. The first mutagen used was ultraviolet radiation; it was replaced by ethylenimine when it became no longer efficient in increasing variability. As new, high producers were isolated, the medium was modified to best suit their requirements for still higher productivity. The critical environmental factors were absence of phosphate and organic salts, concentration of the nitrogen source and ratio organic/inorganic nitrogen, ratio ammonium sulfate/calcium carbonate, and addition of slowly utilizable carbon sources, such as lactose and oil; optimum temperature and initial pH were 25°C and 7.0. Aeration/agitation requirements of improved strains were high. Fermentation was characterized by abrupt pH changes which impaired rapid accumulation of the antibiotic. Antimycin A was produced during both the trophophase and idiophase.

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Fermentation characteristics, previously studied in shake flasks, were reproduced in aerated-agitated fermenters, using three strains of Streptomyces sp. which had been selected for their high antimycin A productivity in shake flasks. Fermentation in fermenters was run in three stages. The medium consisted of soy flour, glucose, ammonium sulfate and calcium carbonate; initial pH was 7.2-7.5, and temperature 25°C.
The course of fermentation was then modified to encourage maximal growth and eliminate the intermediate lag period observed in shake flasks. Useful corrections included continuous addition of soybean oil at 1.25%/day and maintenance of pH at 6 by addition of ammonium hydroxide on demand. The ammonium hydroxide added also served as a rapidly utilized nitrogen source and could not be replaced by NaOH or KOH. Under optimal conditions antimycin A was produced at constant rate from the second to the sixth day, when maximum yields of more than 9 g/liter were attained. A procedure for antimycin A extraction is described.

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One hundred and eight derivatives of mycophenolic acid (MA) have been prepared by modifications at the phenolic hydroxyl and/or carboxyl sites. None of these compounds was as effective as MA in suppressing cell growth of L-5178Y cell in vitro, whereas several compounds with changes at both the hydroxyl and carboxyl groups were more effective than MA against EHRLICH solid carcinoma and L-1210 leukemia in mice.

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Several derivatives of mycophenolic acid (MA) were tested for their antitumor activity against leukemia L-1210 when administered orally and carbamoyl mycophenolic acid ethylester (CMAE) was selected as the most active antitumor agent in these tests. An oral administration of CMAE also inhibited the growth of EHRLICH solid carcinoma, NF sarcoma, myeloma X-5563 and sarcoma 180 in mice. In comparison with antitumor activity of MA, the improvement in activity of CMAE against leukemia L-1210 and EHRLICH solid carcinoma was indeed remarkable. CMAE seems to be less immunosuppressive than MA.

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Incubation of spores, washed mycelium or whole cultures of a Streptomyces sp. with chloramphenicol (I) resulted in the loss of in vitro bioactivity of the antibiotic. Gas chromatographic estimation of an appropriate extract revealed that more than 95% of the antibiotic was inactivated under the specified conditions. The spores inactivated chloramphenicol in an inorganic buffer solution, or in distilled water, without the addition of carbohydrate or external co-factor. However, addition of certain carbon sources to the spores showed a pronounced effect on the chloramphenicol
transformation process and on the relative concentration of the inactivated products. Time-course studies on the spore-catalyzed chloramphenicol transformation activity showed a maximum activity at 12-hour incubation. Addition of glucose or acetate at this point maintained maximum activity. The transformation products were identified as: chloramphenicol-1-acetate (IIa); chloramphenicol-3-acetate (IIb); chloramphenicol-3-propionate (III); chloramphenicol-3-isobutyrate (IV); chloramphenicol-3-butyrate (V); and chloramphenicol-3-isovalerate (VI), by techniques of TLC, CPC, GC, UV, IR, MS and NMR. The microbial characteristics of the isolated
strain include the formation of flexuous gray aerial mycelium with smooth to rough spores, irregular in size. It is an H₂S and melanin former, non-chromogenic, and was inhibited by a streptomycin-producing strain of Streptomyces griseus. The organism was identified as a strain of subspecies of Streptomyces griseus (KRAINSKY 1914) WAKSMAN and HENRICI (1948).

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The mode of action of ASK-753 on Bacillus subtilis was examined. Unlike proper sideromycin antibiotics ferrioxamine B failed to antagonize the antimicrobial effects of ASK-753. The antibiotic could inhibit the biosynthesis of nucleic acids; effect on the RNA was more pronounced. ASK-753 affected the stability of prelabelled DNA of B. subtilis in growing or resting cultures; the effect on the latter was more pronounced. Lysis of B. subtilis protoplasts could be attained at 30°C but not at 4°C which excludes a possible detergent effect of the drug. The drug exerted a potent inhibiting influence on protein synthesis by arresting the activity of lysyl-tRNA synthetase and thus could prevent the incorporation of ₁₄C-lysine.

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During inhibition of protein synthesis by the antibiotic enomycin at less than 5 nM in the reticulocyte lysate system, polyribosomes disaggregated and the 80S ribosomes accumulated. At these concentrations little inhibition of chain elongation and release from the ribosomes was demonstrated. Enomycin caused an increase in the amount of 80S initiation complex as well as the 40S ribosomal subunit-Met-tRNA_f complex. The former complex could react with puromycin under the inhibiting conditions. Val-tRNA binding to the 80S ribosomes was not decreased by the antibiotic. However pactamycin-induced accumulation of the initial dipeptide (fMet-Val) was inhibited when the system was preincubated with enomycin and fMet-tRNA_f. Thus the preferential inhibition of the initial phase of protein synthesis by enomycin is made evident by its inhibition of the initial dipeptide synthesis.

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