The structure of antibiotic eremomycin B

A new biologically active component, antibiotic eremomycin B, was isolated from the culture liquid of Amycolatopsis orientalis subsp. eremomycini, the producing strain for antibiotic eremomycin. Its structure was established by NMR spectroscopy and mass spectrometry. Eremomycin B was shown to differ from eremomycin by the presence of an N-carboxymethyl substituent in the disaccharide eremosamine fragment.     

The structure of the aglycon of eremomycin--a new antibiotic of the polycyclic glycopeptide group

Eremomycin is shown to be a new representative of the group of polycyclic glycopeptides. By the amino acid composition it is close to vancomycin but by the structure of triphenoxytriaminotricarboxylic acid it differs from vancomycin. Monodechlorovancomycinic acid was detected in eremomycin. On the basis of the data obtained in studies on the amino acid sequence and the molecule functional groups the structural formula of eremomycin aglycon was assigned. It is demonstrated that the chlorine-containing phenylserine fragment of monodechlorovancomycin acid is located in the N-end region of the aglycon peptide chain.     

Eremomycin--a new antibiotic of the polycyclic glycopeptide group

Eremomycin is a novel antibacterial antibiotic. It was isolated at the Institute of New Antibiotics, the USSR Academy of Medical Sciences from the culture fluid of actinomycete INA-238. By its physico-chemical and biological properties the antibiotic was classified as belonging to the group of polycyclic glycopeptides. Chemical structure of eremomycin was asserted and it was shown to be a new representative of the group close by its structure to vancomycin and differing from it by the carbohydrate composition and structure of tri-phenoxytriaminotricarboxylic acid. By its anti-bacterial spectrum eremomycin was found to be close to ristomycin and vancomycin. Still, its activity was 2-10 times higher. The antibiotic was several times less toxic than vancomycin. Unlike vancomycin and ristomycin, the novel antibiotic induced no tissue necrosis after its intramuscular administration. The chemotherapeutic indices of eremomycin in treatment of staphylococcal and streptococcal sepsis in albino mice exceeded 10 times those of vancomycin. At present eremomycin is under clinical trials.     

The structure and antimicrobial activity of the partial degradation products of the antibiotic eremomycin

Antimicrobial activity of partial degradation products of eremomycin, a new glycopeptide antibiotic, was studied. The products formed by eremomycin deglycosylation (deseremosaminyl eremomycin, eremosaminyl aglycone and aglycone) and elimination of the chlorine atom from the molecule aglycone moiety (dechloroeremomycin). The spectral data in favour of the compounds structure are presented. It was found that partial degradation led to a decrease in the antimicrobial activity of the antibiotic. Dechloreremomycin had the highest activity among the products. Its MIC for the methicillin-resistant strains of Staphylococcus aureus was only twice as low as that of the initial antibiotic.     

Structure of eremosamine--an amino sugar from the antibiotic eremomycin

A new amino sugar named eremosamine was isolated from hydrolysate of eremomycin, an antibiotic belonging to the group of polycyclic glycopeptides. Crystalline derivatives of the amino sugar i. e. methyleremosaminide and methyl-N,O-acetyleremosaminide (alpha- and beta-anomers) were prepared. The data on PMR study and optic properties of the compounds showed that eremosamine had the structure of 2,3,6-tridesoxy-3-amino-3-C-methyl-L-arabinohexose.     

Study of the activity of a new glycopeptide antibiotic eremomycin combined with tobramycin against Staphylococci in vitro

Eremomycin is an original natural antibiotic with glycopeptide structure isolated at the Institute of New Antibiotics, the USSR Academy of Medical Sciences. Activity of eremomycin alone or in combination with tobramycin was studied with using 25 clinical strains of staphylococci. 56 and 88 per cent of the strains were respectively resistant to gentamicin and kanamycin, two aminoglycoside antibiotics. All the staphylococcal strains were sensitive to eremomycin in concentrations of 0.12 to 1 microgram/ml. The MIC of tobramycin for 10 (40 per cent) sensitive strains ranged within 0.25-2 micrograms/ml. For 60 per cent of the strains the MIC was equal to or higher than 16 micrograms/ml. When eremomycin was used in combination with tobramycin the antibacterial effect with respect to 17 strains (68 per cent) increased. In 32 per cent of the strains the effect was synergistic and in 36 per cent of the strains it was additive. Indifference and antagonism were detected with respect to 7 (28 per cent) and 1 (4% per cent) strains respectively. No significant difference was shown in manifestation of the synergistic-additive nature of eremomycin and tobramycin interaction with respect to the tobramycin sensitive and resistant strains.     

Enzyme immunoassay for the determination of the glycopeptide antibiotic eremomycin

An indirect competitive enzyme-linked immunosorbent assay (ELISA) was developed using rabbit polyclonal antibodies against the eremomycin-glucose oxidase conjugated antigen. This technique allows the glycopeptide antibiotic eremomycin to be determined both in aqueous solutions (with a sensitivity as high as 0.1 ng/ml) and in blood plasma. The cross-reactivity of the antibodies with vancomycin was 0.4% of that for eremomycin, while teicoplanin was almost not recognized. Experiments with blood plasma samples diluted 1: 10 showed that the assay was linear over the concentration range 1–30 ng/ml and that the variation coefficient did not exceed 10%. The high sensitivity and selectivity of this test make it suitable for pharmacokinetic studies and drug monitoring analysis.     

In vitro activity of a new glycopeptide antibiotic eremomycin in relation to obligate anaerobic Gram-positive bacteria]

Antibacterial activity of eremomycin, a novel glycopeptide antibiotic, against obligate anaerobic Gram-positive++ bacteria was studied. Eremomycin was shown to inhibit the growth of obligate anaerobic Gram-positive++ cocci and bacteria belonging to Clostridium in rather low concentrations and within narrow ranges of the MIC which was indicative of the antibiotic undoubted advantages. The antibacterial activity of eremomycin was 2 times as high as that of vancomycin and 8 times as high as that of ristomycin with respect to Gram-positive++ anaerobic cocci. Pathogenic strains of Clostridium spp. were 2 to 4 times more sensitive to eremomycin than to vancomycin. A significant property of the novel glycopeptide antibiotic was shown to be its capacity for inhibiting the growth of Gram-positive++ aerobic and obligate anaerobic cocci within the same concentration ranges which might be of importance in monotherapy of mixed aerobic and anaerobic infections.     

Structure of bacillomycin F, a new peptidolipid antibiotic of the iturin group

The structure of a new antibiotic of the iturin group, bacillomycin F, has been demonstrated. It is a mixture of homologous peptidolipids, essentially C51H80N12O14 and C52N82N12O14. The lipid moiety consists of minor isoC15, anteisoC15 beta-amino acids and major isoC16, isoC17 and anteisoC17 beta-amino acids. The peptide sequence was determined by studying the peptides obtained after mild HCl hydrolysis and by Edman degradation of bacillomycin F treated with N-bromosuccinimide. The sequence was confirmed by two-dimensional NMR spectrometry and fast-atom-bombardment mass spectrometry gave the molecular masses of the homologous compounds. Bacillomycin F is a cyclic peptidolipid; its complete structure is given in the paper.     

Preclinical toxicological study of the new antibiotic eremomycin. Chronic toxicity and effect on intrauterine development of rats

Toxicity of eremomycin was studied after its multiple parenteral administration to albino rats, guinea pigs and dogs in doses equivalent by the body surface to the daily doses for humans i. e. 1 and 3 g. The antibiotic was administered for 1 to 6 months. Tolerance of the antibiotic by the dogs after intravenous and intramuscular administration was satisfactory. In some animals there were observed an insignificant increase in the activity of alanine aminotransferase and a rise in the level of urea in blood serum. Pathomorphological examination of the internal organs of the albino rats and dogs showed that in high doses the antibiotic could have a damaging effect on the kidneys and epithelium of the gastrointestinal tract. The level of the damages depended on the dose of the antibiotic and duration of its use. The damages induced by eremomycin were reversible. It had no marked effect on the peripheral blood count, coagulation system and erythrocyte resistance. In the tested doses the antibiotic had no unfavourable effect on the hearing function in the experiments with guinea pigs. Studies with rats revealed that eremomycin had no teratogenic effect. A slightly pronounced embryotoxic action was observed only after using the antibiotic in doses exceeding more than 12 times the approximate therapeutic dose.     

Gluconimycin,a new antibiotic

Summary A new antibiotic, gluconimycin, was isolated from Streptomyces AS 9. The systematic position of the organism is discussed. Gluconimycin has a polypeptide nature. It contains iron and gluconic acid in its molecule. Thus it has been classified as a member of sideromycins. Gluconimycin is considered from the fast moving type when chromatographed by butanolacetic acid-water. The antibiotic is active against Gram+ve, Gram-ve bacteria and some fungi. The antibiotic exerts high toxicity when injected in mice.     

Synthesis and antibacterial activity of eremomycin esters through the carboxyl group]

Methyl, benzyl and diphenylmethyl esters of the glycopeptide antibiotic eremomycin were obtained by its treatment with corresponding diazoalkanes. The esters have high antibacterial activity but are less active than the parent antibiotic.     

Demonstration of a new amidase acting on glycopeptides

An enzyme preparation from almond emulsin cleaved the peptide-carbohydrate linkage of stem bromelain glycopeptide, Asn-Asn (oligosaccharide)-Glu-Ser-Ser. The resulting products were determined to be an intact peptide, Asn-$\text{Asp}$-Glu-Ser-Ser, and an intact oligosaccharide unit with two moles of N-acetylglucosamine. So far as tested the enzyme hydrolyzed glycopeptides with 3 to 10 amino acids, while both asparagine-oligosaccharide from ovalbumin and Asn-GlcNAc were not. Thus, the enzyme is a new amidase capable of hydrolyzing aspartylglycosylamine linkage in glycopeptides with multiple amino acid residues.     

The structure of the glycopeptides from the fish pathogen Flavobacterium columnare

Proteolytic digestion of the phenol-water extraction product of the fish pathogen Flavobacterium columnare afforded a mixture of glycopeptides in which the oligosaccharide moiety was an unusual hexasaccharide composed of 4-O-methyl-2-acetamido-2-deoxy-D-glucuronic acid (GlcNAcA), D-glucuronic acid (D-GlcA), 2,3-di-O-acetyl-D-xylose (D-Xyl), 2-O-methyl-D-glucuronic acid (D-GlcA), D-mannose (D-Man), and 2-O-methyl-L-rhamnose (L-Rha). By the application of high-resolution 1D and 2D NMR, mass spectrometry, and chemical analysis, the hexasaccharide structure was determined to be: [carbohydrate structure--see text] where all monosaccharides have the D-configuration except for 2-O-methyl-L-rhamnose; and were in the pyranose form. Only one carbohydrate structure was found. The peptide part was represented by tri- to hepta-peptides with a minimal common tripeptide fragment Asp-Ser-Ala, extended with Ala and Val.