In the lipophilic extracts from Streptomyces cinnamomeus 2-ethyl-5-(3-indolyl)oxazole (1a) was detected by chemical screening methods. The structure of the crystalline 1a was determined by spectroscopic and X-ray analysis. The new mono- and dibromo derivatives 1b and 1c are described. 1a is identical with pimprinethine and belongs to a group of microbial indolealkaloids, which can be regarded as masked tryptamine derivatives.
A new antibiotic U-62162 has been isolated from the fermentations of Streptomyces verdensis Dietz, sp. n. (UC-8157). The compound has been characterized and its gross structure has been elucidated. The antibiotic inhibited the growth of Gram-positive bacteria (particularly Staphylococcus aueus) but was inactive in experimentally infected animals.
Novel antibiotic everninomicin D is chemically transformed into new biologically active derivatives. Reactions of a nitro group attached to a tertiary carbon center have been investigated. Synthesis and reactions of hydroxylaminoeverninomicin D, aminoeverninomicin D and their derivatives have been discussed.
The mono- and diformyl gramicidins S have been prepared. Monoformyl gramicidin S retains about 50% of the expected biological activity and the diformyl derivative is inactive. It is therefore, conceivable that both the amino groups equally contribute to the biological activity of the antibiotic. However, monoformyl gramicidin S has been found to form aggregate and this aggregate is more stable under acidic conditions rather than in neutral or alkaline solutions. Denaturing agent urea has been found useful in dissociating the aggregate. The aggregating ability of formyl peptides is at least be due to their formyl groups.
The activities of tobramycin derivatives acetylated and ethylated on the 6'-N, 2'-N and 3-N positions were examined. The MICs of these derivatives against tobramycin sensitive strains indicated that 2'-N-ethylated and 6'-N-ethylated derivatives have a fairly good activity, and confirmed that the 3-N position is the most important one for antibiotic activity since 3-N derivatives were less active. The MICs of these derivatives against tobramycin resistant strains, and their inactivation by tobramycin modifying enzymes were examined. These results showed that 2'-N or 6'-N ethylation protects the drug against inactivation by AAC(2') or AAC(6'), respectively, and 2'-N-ethyltobramycin and 6'-N-ethyltobramycin were active against strains containing these modifying enzymes. On the other hand, 3-N ethylation protects the drug against inactivation by AAC(3) but 3-N-ethyl tobramycin does not inhibit strains containing this enzyme.
Isopenicillin N (I) and penicillin N (II) were separated effectively by reversed phase HPLC as derivatives of chiral 2, 3, 4, 6-tetra- O-acetyl-β-D-glucopyranosyl isothiocyanate (III). This permitted identification of isopenicillin N isolated by HPLC during a biosynthetic cell-free experiment using α-L-aminoadipyl-L-cysteinyl-D-valine (IV) as precursor.
The inhibition characteristics of 25 monocyclic β-lactams mainly with an amido function at C3 have been studied against the β-lactamases produced by 4 bacterial types. Significant levels of inhibition were found for only a few of the compounds tested and primarily against Staphylococcus β-lactamase. The most active inhibitor tested, 3-p-nitrophenylacetamido-4-phenylazetidin-2-one, was found to require a cis geometry, the trans isomer being almost inactive.
The structures of 16, 17-dihydrorifamycin S and 16, 17-dihydro-17-hydroxyrifamycin S, two novel ansamycins from the recombinant strain C 5/42 of Nocardia mediterranei, were elucidated by physico-chemical methods. In addition structure-activity relationships among 16, 17-hydrogenated rifamycins are discussed.
Biosynthetic studies of the antibacterial and antitumor antibiotics vineomycins A1 (1) and B2 (2), produced by Streptomyces matensis subsp. vineus, were carried out by labeling experiments with [1-13C]- and [1, 2-13C2]sodium acetate followed by 13C NMR spectroscopy. The results show that the benz[a]anthraquinone chromophore of 1 is derived from a decacetate metabolite with decarboxylation at the carboxyl end and that 2 is formed via C-C bond cleavage of 1. Isolation of rabelomycin from the fermentation broth of the same strain suggests a close biosynthetic relationship among the simple benz[a]anthraquinone antibiotics such as rabelomycin, tetrangomycin, aquayamycin, a C-glycosylated benz[a]anthraquinone, and vineomycins. These biosynthetic data prompted us to reconsider the previously published structure of the antibiotic SS-228Y, which has now been revised.
Two novel autoregulators affecting the cyto-differentiation of anthracycline-producing Streptomyces griseus have been isolated from cultures of aerial mycelium-forming progenitor strains and blocked mutants. By spectral (IR, CD, MS, 1H and 13C NMR) methods, the autoregulators are shown to be the diastereomers of 4, 5-dihydroxydecanoic acid-4-lactone. Two novel autoregulators affecting the cyto-differentiation of anthracycline-producing Streptomyces griseus have been isolated from cultures of aerial mycelium-forming progenitor strains and blocked mutants. By spectral (IR, CD, MS, 1H and 13C NMR) methods, the autoregulators are shown to be the diastereomers of 4, 5-dihydroxydecanoic acid-4-lactone.
Effects of arginine on gramicidin S (GS) biosynthesis were investigated by growing Bacillus brevis ATCC 9999 in a synthetic medium consisting of 10 g fructose, 0.15 g L-proline, 1.3 g L-histidine, 1.3 g L-glutamine, 0.5 g L-methionine, 1 g L-phenylalanine and six mineral salts per liter. Supplement of 3 g/liter L-arginine to the medium, especially at the logarithmic phase of growth, enhanced the cell growth and GS production. Twice supplement of 3 g/liter arginine at the begining and middle logarithmic phase of growth gave much more GS production than any once supplement, but the soluble GS synthetase extractable by lysozyme digestion was remarkably decreased. However, the decrease of enzyme by arginine seemed to be merely an apparent phenomenon, because GS-synthesizing ability of the cell was strongly enhanced by arginine and the enzyme which was not extracted by lysozyme digestion could efficiently be solubilized by ultrasonic homogenization. In the soluble fraction of cells grown in an arginine-added synthetic medium, no arginine was detected, but a large amount of ornithine was accumulated. When L-ornithine, instead of L-arginine, was added to the synthetic medium, cell growth and GS production were stimulated with increase of its concentration without decrease in the soluble enzyme activity.
A selective isolation medium was devised for Pseudomonas bacteria. An antibiotic mixture which contained 10 μg per ml of cerexin A, 10 μg per ml of nalidixic acid and 30 μg per ml of cycloheximide was used. With this antibiotic medium, 58 strains of bacteria presumed to be Pseudomonas which were subdivided into 18 taxonomically different groups were isolated from 3 soil samples with 9% of contaminants. With this method, it was possible to isolate a Pseudomonas bacterium from a sample containing about 400 times as many other Gram-positive and -negative bacteria.
Bacillus circulans NRRL B-3312 produces the aminoglycoside antibiotic butirosin and encodes an aminoglycoside 3'-phosphotransferase. We detected a 48 kilobase plasmid, pIP850, in this strain; this was analyzed by agarose gel electrophoresis following digestion with EcoRI restriction endonuclease and by nucleic acid hybridization. The results obtained indicate that plasmid plP850 does not carry the structural gene for the aminoglycoside modifying enzyme.