Modification of glycopeptide antibiotic eremomycin by the action of alkyl halides and study on antibacterial activity of the compounds obtained.

Alkylation of glycopeptide antibiotic eremomycin by the action of different alkyl halides leads, depending on the structure of alkyl halides used, to eremomycin derivatives of six types; alkylated at the N-terminus, quaternary compounds at the N-terminus, eremomycin esters, esters of eremocycin alkylated at the N-terminus, esters of eremomycin quaternised at the N-terminus, esters of eremomycin alkylated both at the N-terminus and at the aminogroup of disaccharide branch. Five compounds demonstrated high antibacterial activity in vitro, N-allyleremomycin and methyl ester of N,N-dimethyleremomycin being at least as good as the parent eremomycin.

Synthesis and biological activity of derivatives of glycopeptide antibiotics eremomycin and vancomycin nitrosated, acylated or carbamoylated at the N-terminal.

Nitrosation, carbamoylation or acylation of the glycopeptide antibiotics eremomycin or vancomycin produced series of derivatives substituted at the N-terminus of the peptides. Though the modified amino group in these derivatives is not capable of protonation, N-nitroso derivatives retain antibacterial activity in vitro and in vivo. N-Carbamoyleremomycin has low activity, and N-Cbz-eremomycin and N-Boc-eremomycin are devoid of antibacterial activity, both in vitro and in vivo.

[Synthesis and antibacterial activity of eremomycin esters through the carboxyl group]. / Sintez i antibakterial'naia aktivnost' éfirov antibiotika po karboksil'noi gruppe.

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.

[Study of the activity of a new glycopeptide antibiotic eremomycin combined with tobramycin against Staphylococci in vitro]. / Izuchenie aktivnosti sochetaniia novogo glikopeptidnogo antibiotika éremomitsina s tobramitsinom v otnoshenii stafilokokkov 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.

[Glycopeptide antibiotics: eremomycin, vancomycin, and teicoplanin. Comparison of several parameters of pharmacokinetics and antimicrobial activity]. / Glikopeptidnye antibiotiki: eremomitsin, vankomitsin i teikoplanin. Sravnenie nekotorykh parametrov farmakokinetiki i antimikrobnoi aktivnosti.

Pharmacokinetic parameters of eremomycin (Institute of New Antibiotics, the USSR Academy of Medical Sciences), teichoplanin (Lepetit) and vancomycin (Eli Lilly) were compared after their intravenous administration to rats in the same dose of 50 mg/kg. It was shown that the area under the concentration time curve of eremomycin was 2 times smaller than that of teichoplanin and 6 times larger than that of vancomycin. The mean retention time of eremomycin was close to that of teichoplanin and 1.6 times higher than that of vancomycin. Bioavailability of eremomycin and teichoplanin after their extravascular administration was the same and amounted to 94 per cent. Antibacterial activity of eremomycin against methicillin resistant strains of staphylococci was 4 times higher than that of teichoplanin and vancomycin.

[In vitro activity of a new glycopeptide antibiotic eremomycin in relation to obligate anaerobic Gram-positive bacteria]. / Aktivnost' in vitro novogo glikopeptidnogo antibiotika éremomitsina v otnoshenii obligantnykh anaérobnykh gram- polozhitel'nykh bakterii.

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.

[The structure and antimicrobial activity of the partial degradation products of the antibiotic eremomycin]. / Struktura i antimikrobnaia aktivnost' produktov chastichnoi degradatsii antibiotika éremomitsina.

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.

[Comparison of carminomycin and rubomycin action on the dynamics of the immune response to the T-independent Vi-antigen of S. typhi]. / Sravnenie deistviia karminomitsina i rubomitsina na dinamiku T-nezavisimomu Vi-antigenu S. typhi.

The effect of carminomycin and rubomycin on the dynamics of the primary immune response to T-independent Vi-antigen of S. typhi was studied. Differences in the character of the antibiotic effect indicative of the high selective effect of carminomycin on the multiplying cells or precursors of the antibody forming plasmocytes were noted. It was found that the carminomycin inhibitory effect on synthesis of hemagglutinins to Vi-antigen was higher than that to sheep red blood cells. Carminomycin was shown to impair the formation of the immunological memory, while rubomycin did not suppress the development of the "memory cell" clone to T-independent antigen.

[Action of doxorubicin on immunogenesis]. / Deistvie doksorubitsina na immunogenez.

The effect of doxorubicin, carminomycin and rubomycin on some immunological reactions was studied comparatively on mice. It was shown that doxorubicin had an immunodepressant effect on the synthesis of antibodies and antibody-forming cells. By the character of its immunodepressant effect doxorubicin was similar to rubomycin. In a dose of 0.3 of the LD50 doxorubicin had no effect on the transplantation immunity in the system of "transplant versus host" and did not prolong the lifetime of the skin graft.

[Comparative study of the effects of carminomycin 13-cyclohexylidenehydrazone and carminomycin on several immunologic responses of the body]. / Sravnitel'noe izuchenie vliianiia 13-tsiklogeksilidengidrazona karminomitsina i karminomitsina na nekotorye immunologicheskie reaktsii organizma.

The effect of carminomycin and 13-cyclohexylidenhydrazone of carminomycin (13-CHC) on some immunological reactions was studied comparatively on mice. It was shown that 13-CHC administered intravenously or orally had an immunodepressive effect on the synthesis of the antibodies to the sheep red blood cells. By the character of the immunodepressive effect on the humoral and transplantation immunity 13-CHC was close to carminomycin. It had an inhibitory effect on the transplantation immunity, prevented the mice from death in the "graft-versus-host" system and increased the life-span of the cutaneous flaps.

[Study of the effect of rifampicin on certain immunological and protective reactions of the body]. / Izuchenie vliianiia rifampitsina na nekotorye immunologicheskie i zashchitnye reaktsii organizma

The effect of rifampicin on formation of hemagglutinins in mice in response to administration of sheep erythrocytes was studied. The experiments showed that rifampicin administered orally in doses 10-25 times higher than the therapeutic ones did not suppress formation of the antibodies and protective mechanisms of the organism. The antibiotic did not lower the absorbing capacity of the cells by the reticuloendothelial system and the rate of phagocytosis by the leucocytes of the peritoneal exudate in mice. Rifampicin had no effect as well on adaptation of a skin homotransplant in the animals.

[Effect of the peroral use of the antitumor antibiotic, carminomycin, on the immunological reactivity of the body of animals]. / Vliianie peroral'nogo primeneniia protivoopukholevogo antibiotika karminomitsina na immunologicheskuiu reaktivnost' organizma zhivotnykh

Carminomycin administered orally to mice for many times in doses of 2.5 and 1.25 mg/kg induced suppression of hemagglutinine production to sheep erythrocytes and formation of immunologically competent cells in the spleen of test animals. The content of DNA and RNA in the spleen of the test animals treated with carminomycin and sheep erythrocytes was somewhat lower than that in the control mice immunized but not treated with the antibiotic. Carminomycin prolongated the life time of the skin graft by 6.5 days as compared to that of the skin homotransplant in the control animals. The oral use of carminomycin in a dose of 2.5 mg/kg induced a statistically significant decrease in the absorption capacity of the cells of the reticuloendothelial system of the animals.

[Comparative study of the antibacterial activity of aminoglycoside antibiotics and their combinations with carbenicillin against Pseudomonas aeruginosa]. / Sravnitel'noe issledovanie antibakterial'noi aktivnosti antibiotikov-aminoglikozidov i ikh kombinatsii s karbenitsillinom v otnoshenii sinegnoinoi palochki.

Antibacterial activity of 7 aminoglycoside antibiotics and combinations of tobramycin or gentamicin with carbenicillin was studied with respect to 33 clinical strains of Ps. aeruginosa. Tobramycin, sisomicin, gentamicin and amicacin showed high levels of antibacterial activity. Tobramycin and sisomicin were 3-4 and 2 times more effective than gentamicin. 100 per cent of the Ps. aeruginosa isolates was sensitive to tobramycin and amicacin. The number of the isolates sensitive to sisomicin and gentamicin amounted to 97 and 94 per cent respectively. The respective numbers for streptomycin and kanamycin were 32 and 11 per cent. No monomycin sensitive isolates were detected. Combination of tobramycin or gentamicin with carbenicillin increased the antibacterial activity of the aminoglycoside antibiotics by 2-16 times and that of carbenicillin by 2-32 times. The synergistic effect of gentamicin or tobramycin with carbenicilin was observed with respect to 50 and 58 per cent of the isolates respectively. No antagonistic effect was detected on the combined use of the antibiotics. The majority of the isolates (96 per cent) were sensitive to combinations of carbenicillin in a concentration of 50 micrograms/ml with tobramycin or gentamicin in concentrations of 0.15 or 0.3 micrograms/ml respectively.

[Effectiveness of the combined use of tobramycin with carbenicillin or cephalosporins in experimental infection in mice caused by Providencia stuartii]. / Effektivnost' kombinirovannogo primeneniia tobramitsina s karbenitsillinom ili tsefalosporinami pri éksperimental'noi infektsii u myshei, vyzvannoi Providencia stuartii.

Antibacterial activity of tobramycin in combination with carbenicillin or cephalosporins against 20 strains of Providencia stuartii was studied. The combinations of tobramycin with carbenicillin (1 : 2.5) or cephaloridine (1 : 1) were most active. The MIC of tobramycin used in combination with carbenicillin or cephaloridine decreased 3-30 times. In treatment of albino mice with sepsis caused by Providencia stuartii it was possible to lower 2-8 times the dose of tobramycin used in combination with carbenicillin or cefazolin.

[Pharmacokinetic study of eremomycin in an experiment]. / Izuchenie farmakokinetiki éremomitsina v éksperimente.

Pharmacokinetics of eremomycin, a novel original glycopeptide antibiotic was studied. It was shown that after a single intravenous or subcutaneous administration to mice, rabbits and dogs eremomycin concentrations in blood and duration of the antibiotic circulation depended on the dose level and administration route. After subcutaneous or intramuscular administration eremomycin was rapidly absorbed and detected in serum even in 15-30 min. The maximum levels were observed in 2 hours. Absolute bioavailability after subcutaneous administration averaged to 85 per cent. Eremomycin penetrated into organs. The antibiotic concentrations in cerebrospinal fluid were low. The highest concentrations of eremomycin were detected in the kidneys, lungs and spleen. The antibiotic mainly excreted with urine. The renal clearance amounted to 85 per cent of the total clearance. 2-3-month exposure of dogs and rats to eremomycin in doses 4-10 times higher than the approximate single therapeutic doses for humans (250 mg) resulted in cumulation of the antibiotic.

[Toxicity and antimicrobial properties of the new aminoglycoside antibiotic 535]. / Izuchenie toksichnosti i antimikrobnykh svoistv novogo aminoglikozidnogo antibiotika 535.

LD50 of antibiotic 535 (3'-desoxykanamycin C) on its intravenous, subcutaneous and oral administration to albino mice was 225, 1150 and at least 5000 mg/kg respectively. After a single subcutaneous administration to rabbits in a dose of 10 mg/kg antibiotic 535 was rapidly absorbed and detected in the blood and organs of the animals for 24 hours. The antibiotic was mainly excreted with the urine. Comparative investigation of the pharmacokinetics of antibiotic 535, tobramycin and kanamycin in rabbits revealed no significant differences. Antibiotic 535 showed a broad antibacterial spectrum and inhibited both grampositive and gramnegative bacteria. It was highly active against infections caused by S. aureus, E. coli and Pr. vulgaris and somewhat less active against infections caused by Ps. aeruginosa. In treatment of experimental tuberculosis of albino mice antibiotic 535 and tobramycin were inferior by their efficacy to kanamycin.

[Rapid change in the dynamics of antibody-forming cells under the influence of a single injection of various anthracyclines]. / Bystroe izmenenie dinamiki antiteloobrazuiushchikh kletok pod vliianiem odnokratnoi in''ektsii razlichnykh antratsiklinov.

The dynamics of the titers and number of the antibody forming cells was studied within 26 hours after a single injection of anthracycline to immunized animals at various phases of the immune response. The specificity of the "rapid" effect of anthracyclines suggests that the low differentiated precursors of the antibody forming cells are the main target for the rubomycin effect and the immune competent cells in the state of multiplication and differentiation under the effect of the antigen are the main target for the carminomycin effect. The study was performed with noninbred mice immunized with sheep red cells.

[Comparison of the action of carminomycin and rubomycin on the dynamics of the primary and secondary immune responses]. / Sravnenie deistviia karminomitsina i rubomitsina na dinamiku pervichnogo i vtorichnogo immunogo otveta.

The effect of rubomycin and carminomycin on the dynamics of the primary and secondary immune response and formation of the immunologic memory to sheep red cells in mice was studied. Differences in the character of the antibiotics effect indicative of the higher selective action of carminomycin on multiplying cells, precursors of the antibody-forming plasmids, were found. Theoretically interesting discrepancies in the effect of the antibiotics on the content of the antibodies in the serum and the antibody-producing cells in the spleen were shown. It was demonstrated that carminomycin had no effect on formation of the immunologic memory inspite of a noticeable decrease in the total number of the spleen nuclear cells and the number of the antibody-forming cells at the moment of immunization under the effect of the antibiotic.

[Immunodepressive action of carminomycin and rubomycin derivatives]. / Immunodepressivnoe deistvie proizvodnykh karminomitsina i rubomitsina.

The immunodepressive effects of carminomycin and its 3 semi-synthetic derivatives, as well as rubomycin and its derivative R-103 were compared. It was found that 14-hydroxycarminomycin was much superior to the other substances in the experiments with synthesis induction suppression of antibodies against sheep red cells in mice. Suppression of the rejection of the skin allogenic grafts in the mice by carminomycin was higher as compared to that by the other substances. Probably different populations of the immune competent cells have selective sensitivity to separate anthracyclines.