Two new antibiotics, cervinomycin A1 and A2, were isolated from the culture filtrate of strain AM-5344, a soil isolate. The strain was found to belong to a new species of the genus Streptomyces for which the name Streptomyces cervinus is proposed. The antibiotics possess a strong inhibitory activity against anaerobic bacteria, such as Clostridium perfringens, Peptococcus prevotii and Bacteroides fragilis.
In our continued search for the production of β-lactam-containing molecules from bacteria, we report the isolation and structure determination of a simple carbapenem SQ 27, 860, produced by species of Serratia and Erwinia. The antibiotic is highly unstable and isolation was achieved through the p-nitrobenzyl ester.
The 4''-O-substituted tylosin derivatives were prepared by selective esterification of the 4''-OH, and relationships between the substituent groups and antimicrobial activity against macrolide-resistant strains were examined. Introduction of branched-chain aliphatic acyl groups such as 2-methoxyisovaleryl or 4-methylvaleryl group afforded derivatives with good antibacterial activity; MIC values were 12.5 μg/ml against Staphylococcus aureus MS-8710. MIC values of tylosin, erythromycin and josamycin against this strain were 800 μg/ml or more. Further improved activity was obtained by introduction of aromatic groups such as phenylthioacetyl, phenylsulfonylacetyl, 4-nitrophenylacetyl, 4-nitrophenylsulfonyl and phenylethanesulfonyl groups; MIC values were 6.25 μg/ml. These derivatives had also an improved antimycoplasmal activity; MIC values were 0.08μg/ml against macrolide-resistant strains of Mycoplasina gallisepticum. MIC values of tylosin against these strains were from 2.5 to 10μg/ ml. Introduction of the groups described above into the 4''-OH was confirmed to increase the uptake by a resistant strain.
The resistance of Staphylococcus aureus MS-9610 to tylosin and 3-O-acetyltylosin was due to the decreased affinity of its ribosome system to these macrolides. However, 3-O-acetyl-4''-3-O-isovaleryltylosin was found to bind to ribosomes of the strain about three times more than 3-O-acetyltylosin. This binding was not interfered by tylosin and 3-O-acetyltylosin. The 4''-O-acyl group and the mycinose moiety were suggested to have an important role in the binding of tylosin derivatives to ribosomes of resistant strains.
Biotransformation of a macrolide antibiotic and a related compound was studied using various macrolide-producing microorganisms grown in the presence of cerulenin, an inhibitor of de novo synthesis of the aglycone moiety. Protylonolide (1) was transformed into 5-O-(4'-O-propionylmycarosyl)protylonolide (2) by a leucomycin-producing strain, Streptoverticillium kitasatoensis KA-429. M-4365 G2 (3) was bioconverted into M-4365 G3 (4), 9-dihydro M-4365 G3 (5), 3-O-acetyl M-4365 G3 (6) and 3-O-acetyl-9-dihydro M-4365 G3 (7) by a spiramycin-producing strain, Streptomyces ambofaciens KA-1028. Forosaminylated derivatives of M-4365 G2 were not obtained using this microorganism. M-4365 G2 was converted into 3-O-acetyl M-4365 G2 (8) by Stv. kitasatoensis strain KA-429 and a carbomycin-producing strain, S. thermotolerans KA-442. These results suggest that the substrate specificity of mycaminose-and forosamine-binding enzymes is high in Stv. kitasatoensis and S. ambofaciens, respectively, while that of the 3-hydroxyl acylating enzyme and mycarose-binding enzyme is low in these microorganisms. The bioconversion products showed lower antibacterial and antimycoplasmal activities than those of M-4365 G2.
The preparation of 2-deoxy-3-demethoxyfortimicin A (4) from 1, 2', 6'-tri-N-benzyloxycarbonyl-3-O-demethylfortimicin B (5) is described. The overall in vitro antibacterial activity of 4 against a variety of organisms was almost twice that of fortimicin A.
3'-Deoxybutirosin A (4), 5"-amino-3', 5"-dideoxybutirosin A (6), and 5"-amino-4', 5"-dideoxybutirosin A (7) were prepared by deoxygenation of the appropriate hydroxyl in suitably protected derivatives of butirosin A, using sequentially trifluoromethylsulfonylation, displacement with benzenethiolate, and hydrogenolysis. The structures of the compounds were confirmed by NMR spectroscopy, using 13C NMR and 1H NMR at up to 600 MHz. The compounds are broad-spectrum antibiotics active against resistant microorganisms which i n activate butirosin and related aminoglycosides by 3'-phosphorylation.
The antitumor activity of a new antibiotic, stubomycin, against various murine tumors was studied. Stubomycin showed antitumor activity against Sarcoma 180, IMC-carcinoma and Meth-A tumor. In particular, all of the mice inoculated i.p. with IMC-carcinoma were cured when they were given nine successive injections of stubomycin. Stubomycin also showed remarkable antitumor effects against Sarcoma 180 and Ehrlich ascites carcinoma when administered concomitantly with bleomycin.
Mutants of Candida albicans resistant to aculeacin A, a yeast cell-wall inhibitor, were is olated after mutagenesis with ultraviolet light. The parental strain was sensitive to 0.1 -0.5 tig/ml of the antibiotic. In contrast, the minimum inhibitory concentration for the mutants ranged from 50 to 200 μg/ml. Except for papulocandin, another cell-wall inhibitor, the antibiotic susceptibility of the mutants was similar to the parental strain. The parent strain and the aculeacin resistant mutants exhibited similar morphological changes at subinhibitory levels of aculeacin and had comparable growth rates on complex media. The lipid and sterol content of the parent and the mutants were significantly different. For example, the total lipid content was two-fold higher in the mutant strains. Drug resistance in the mutants was specific for aculeacin and papulocandin and appeared to be associated with alteration in the lipid composition of membranes.
The introduction of the methoxyimino group next to the carbonyl of the 7-position side chain in some alkylthioacetamido and vinylenethioaeetamido cephalosporins, and its effect on the in vitro antimicrobial activity, are described.
After injection into mice and dogs, PS-5 showed a very rapid decrease in its blood concentration, compared with cefazolin. Using in vitro experiments with tissue homogenates and acetone powder preparations, the kidney was found to be the primary site of PS-5-inactivation, although the extent of the inactivation varied depending on the species of animals. The comparative stability data of PS-5, NS-5 (deacetylated PS-5), thienamycin and N-formimidoylthienamycin in kidney homogenates of mouse, rabbit, dog and man are presented. Bilateral nephrectomy and the injection of ethylenediaminetetraacetate seemed to prolong the survival t i m e of PS-5 in rats and mice respectively.
A factor responsible for the in vivo metabolism of PS-5 was isolated from the microsomal fraction of the rat kidney. This factor, which did not attack penicillins and cephalosporins, was enzymologically identified with particle-bound renal dipeptidase. Under the action of this factor, PS-5 was inactivated to give three products designated PS-5D I, PS-5D II and PS-5D III.
The chemical structure of PS-5D III, the primary breakdown product of PS-5 by particlebound renal dipeptidase, is elucidated to be 3-(2-acetoamidoethyl)thio-5-(l-carboxypropyl)-1-pyrrolinc-2-carboxylic acid.
The pharmacokinetics and metabolic fate of cefmetazole (CS-1 170, CMZ) were studied in cynomolgus monkeys by means of combination of radio- and bioassay techniques and that of three radioactive drugs labeled at the different moiety of the molecule. The plasma level of radioactivity after intramuscular injection of cefinetazole[methoxyl-14C] (50 mg/kg) reached the maximum level (185μg/ml) after 10 minutes and declined with a half-life of about 48 minutes. In the thin-layer chromatography of the plasma extracts, a single radioactive spot was detected corresponding to unchanged cefmetazole. Repeated intravenous administration for one and t w o weeks showed no effect on the plasma levels and half-lives. More than 75 % of the intravenous or intramuscular dose was recovered in the urine by both radio- and bioassay, the most part being excreted during the first 3 hours period. On the TLC of urine, 93-97% was detected as unchanged cefmetazole. In the bile, the most part (>80%) was detected as unchanged cefmetazole. In the feces, about 15 % of the dose was recovered, in which 30-40 %. was detected as intact cefmetazole. The metabolic fate of [3-35S] and [7-35S]cefinetazole was described and discussed. The whole-body autoradiography in the monkeys was also presented.
Oxanosine, a novel nucleoside, inhibits the growth of Escherichia coli K-12 on peptone agar, but not on Nutrient agar. This antibiotic activity was found to be bacteriostatic and was antagonized by guanine, guanosine, and guanylic acid. The growth of leukemia L 1210 cell was also inhibited by oxanosine, and the inhibition was reversed by guanylic acid. Oxanosine was confirmed to be a competitive inhibitor of GMP synthetase (E.C. 126.96.36.199) and the Ki value was 7.4×10-4 M.