Hybrid Antibiotics Based on Azithromycin and Glycopeptides: Synthesis and Antibacterial Activity.

A series of hybrid antibiotics on the basis of azithromycin and glycopeptides with the glycopeptide molecule attached via the aminoalkylcarbamoyl spacer to 11-position of the macrolide was synthesized. All the synthesized compounds demonstrated equal or superior to azithromycin and vancomycin antibacterial activity against 7 tested strains of grampositive bacteria. The new hybrid antibiotics were more active than azithromycin or vancomycin against S.pneumoniae ATCC 49619. Some of the compounds were active against E.faecium and E.faecalis strains resistant to vancomycin.

[Design of Novel Carboxamides of Eremomycin and Vancomycin with 4- or 3-Amino Methyl Phenyl Boric Acid and Their Investigation].

Amidation of the end carboxyl group of eremomycin and vancomycin by pinacolinic 4- or 3-amino methyl phenyl boron acids esters in the presence of the condensing reagent PyBOP resulted in formation of novel carboxamides of the antibiotics (IIIa-VIa). After elimination of the pinacolinic group under mild hydrolysis in weak acid aqueous medium there formed the respective derivatives with a residue of the nonprotected boric acid (III-VI). It was shown that the activity of the 4-substituted derivatives of the borole-containing eremomycin and vancomycin practically was the same as that of the initial antibiotics, while higher than that of the respective 3-substituted derivatives of the borole-containing derivatives against 8 strains of grampositive bacteria.

[Antimicrobial Properties of Eremoxylarin A Produced by Ascomycete of Sordariomycetes in Submerged Culture].

The fungal strain INA 01108 producing antibiotic substances with broad spectrum of antibacterial activity was isolated from the natural environment. By the morphological characteristics and DNA analysis it was shown to belong to Ascomycetes of Sordariomycetes. In submerged culture the strain produced at least four antibiotics. The major component of them was identified as eremophilane-type sesquiterpene eremoxylarin A. Eremoxylarin A is effective in vitro against grampositive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin group glycopeptide antibiotics resistant Leuconostoc mesenteroides VKPM B-4177. The efficacy and toxicity of eremoxylarin A was determined on a murine staphylococcal sepsis model. The dose of 6.25 mg/kg provided 100% recovery and survival of the animals, while the dose of 3.12 mg/kg was close to the ED50. The chemical structure of eremoxylarin A allows to modify the antibiotic and such studies may be relevant to design a less toxic derivative without loss of the valuable antimicrobial properties.

Regioselective acylation of congeners of 3-amino-1H-pyrazolo[3,4-b]quinolines, their activity on bacterial serine/threonine protein kinases and in vitro antibacterial (including antimycobacterial) activity.

It was found by virtual screening that 3-amino-1H-pyrazolo[3,4-b]quinolines could have wide protein kinase inhibitory activity. Amides of titled amines and thioureas were synthesized regioselectively. 3-Amino-7-methoxy-1H-pyrazolo[3,4-b]quinoline demonstrated in vitro significant inhibitory activity on bacterial serine/threonine protein kinases (inhibition of resistance to kanamycin in Streptomyces lividans regulated by protein kinases). The studies of Structure Activity Relationship (SAR) showed that the substitution of the NH2 group and 1-NH of pyrazole ring or aromatic ring at the position 6 decreased or removed inhibitory activity.

[Fortification of antimicrobial barrier of the small intestine in newborn mice after oral administration of ascorbigen].

Ascorbigen, a natural product, is an indole derivative of L-ascorbic acid. Its effect on postnatal development and antibacterial resistance of the small intestine was studied on newborn mice. Ascorbigen was administered to 3-5-day old mice in a dose of 100 mg/kg orally every day for 7-10 days. 30 minutes before the last administration of the drug clinical isolates of Staphylococcus aureus or Escherichia coli were administered intragastrically to the young mice. The animals were killed in 24 hours and the frequency of the isolation of the microbes from the blood, spleen, kidneys and liver was developed. The oral use of the drug normalized the intestinal microflora, provided a reliable decrease of the bacteria isolation from the blood, spleen, kidneys and liver and prevented the animal death. The morphological examination showed that ascorbigen significantly increased the number and activity of the Paneth cells in the gland crypts, the goblet cells in the villi and mononuclear cells in the selfplate of the intestine mucous membrane vs. the intact control.

[The immunological consequences of congenital infections]. / Immunologicheskie posledstviia vrozhdennykh infekstii.

Mice of different strains were inoculated with type A influenza virus or Mycoplasma arthritidis in the second half of pregnancy. A part of the animals born after this inoculation were characterized by a sharp retardation of growth. The study of the immune status of such animals revealed that their proliferative response to mitogenic/superantigenic factors of the infective agents introduced during pregnancy was suppressed or absent, and the cells of their immune system began to recognize syngeneic intact stimulators in the mixed lymphocytes culture as heterogeneous ones. The spleen of the experimental animals was found to contain suppressor cells, both specific and nonspecific with respect to the infective agent. After inoculation with M. arthritidis areactivity was observed only in mice, sensitive to mycoplasmal superantigen. The data thus obtained suggest that the penetration of infecting agents producing mitogenic/superantigenic factors induced changes in the immune system, contributing to the persistence of the infective agent in the host body.

The Possible Immunological Mechanisms of Pathology in Mice with Congenitally Acquired Influenza Infection.

The fact that congenitally acquired viral infection often strongly influences specific and non-specific immunoreactivity is well documented. Viral infection of pregnant female may lead to serious of pathological consequences for the offspring, namely, to mortality, developmental disorders and in less severe cases to body growth retardation, wasting syndrome and immunodeficiency. In this connection, we have studied congenitally acquired influenza infection in CII mice. The progeny of C57BL/6 female mice, which were infected with influenza virus (A/WSN) by the 3rd week of pregnancy, exhibited a profound growth retardation and major morphological lesions of central nervous system, lymphoid and other organs. We have found out that mice with congenitally acquired influenza infection had autoreactive killer T cells in their lymphoid organs. CII mice exhibited some features of chronic immune activation, namely elevated spontaneous proliferation, spontaneous development of plaque forming cells, and spontaneous inhibition of migration activity. Lymphoid cells from mice with congenitally acquired influenza infection induced an enlargement of regional lymph nodes after they had been injected into syngeneic non-infected recipient in popleteal node assay. The level of this reaction depended on the level of virus-bearing cells in donor cell population and correlated with the increase of gammadelta and CD4(+) T cells. The role of these interactions in pathology is discussed herein.

[Experimental influenzal and tuberculous infections under conditions of specific and nonspecific immunosuppression]. / Eksperimental'naia grippoznaia i tuberkuleznaia infektsii v usloviiakh spetsificheskoi i nespetsificheskoi immunosupressii.

The course of influenza and tuberculosis infections under the conditions of disturbances in the immune response of experimental animals has been studied. As revealed in the survival test, the induction of secondary T- and B-cell-mediated immunodeficiency in mice leads to an increase in the sensitivity of the body to influenza virus, especially in cases of T-cell-mediated immunodeficiency. The injection of BCG in combination with cyclophosphamide into mice induces tolerance to this antigen in the animals; this tolerance has a "split" character, i.e. it affects only T-cell-mediated, but not humoral immunity. The induction of T-cell-mediated immunodeficiency or tolerance to BCG in mice has been shown (in the survival test) to lead to the development of the sensitivity of the animals to experimental tuberculosis infection. B-cell-mediated immunodeficiency did not influence the animal survival rate.

[The humoral immunity system of mice with experimental slow influenzal infection]. / Sostoianie sistemy gumoral'nogo immuniteta u myshei pri éksperimental'noi medlennoi grippoznoi infektsii.

The status of the interferon system and level of immunoglobulins were studied in C57BL6 mice with slow influenza infection. These mice showed signs of immunosuppression: low endogenous interferon production, synthesis of alpha- and gamma-interferon by splenocytes of these mice in vitro 4-8 times lower than by those of the controls, lower levels of IgG in the blood serum. These data indicate general suppression of humoral immunity.

[The use of T-activin for the prevention of congenital influenzal infection in mice and the correction of the immune deficiency]. / Ispol'zovanie T-aktivina dlia profilaktiki vrozhdennoi grippoznoi infektsii u myshei i korrektsii immunodefitsita.

Viremia accompanying influenza infection and the possibility of transplacental passage of the virus into the fetus make it expedient to develop measures for the prophylaxis of intrauterine infection of the fetus in case of influenza during pregnancy. The work presents the optimum scheme of administration of T-activin for prophylactic purposes to pregnant mice with acute influenza infection. Besides, the use of T-activin for immunocorrection in case of established congenital influenza infection in mice is proposed.

[Characteristics of immune reactions to the influenza virus in mice with a slow influenzal infection]. / Osobennosti immunnykh reaktsii na virus grippa u myshei pri medlennoi grippoznoi infektsii.

It had previously been shown that intrauterine infection of mice with influenza virus resulted in growth retardation and significant immunosuppression to various nonspecific agents and influenza virus. The present study demonstrated that such mice also had lower production of specific antibody and reduced capacity to form the delayed hypersensitivity to influenza virus. Despite the lack of specific immune response, such mice had high levels of response to influenza virus in adoptive transfer. The reasons for which lymphocytes of mice with slow influenza infection fail to manifest their immunological potentials in situ require further study.

[Morphometric analysis of immunologic deficiency in newborn mice developing after transplacental transmission of live or inactivated influenza A virus]. / Morfometricheskii analiz immunologicheskoi nedostatochnosti u myshat, razvivaiushcheisia v rezul'tate transplatsentarnoi peredachi zhivogo ili inaktivirovannogo virusa grippa.

Morphometric evaluation of the thymus and spleen was used to characterize the complex immunological deficiency in suckling mice developing as a result of transplacental transmission of both live and inactivated influenza virus.

[The role of suppressor cells in congenital influenza infection in mice]. / Rol' supressornykh kletok pri vrozhdennoi gippoznoi infektsii u myshei.

Young mice with congenital influenza infection have lower immune responsiveness of lymphocytes to nonspecific mitogens and influenza virus antigens. Lymphocytes of such animals inhibit proliferation of normal lymphoid cells activated with concanavalin A and immune lymphocytes activated with influenza virus antigens. It is assumed that in congenital influenza infection one of the possible mechanisms of immunosuppression in mice is the activation of suppressor T-cells.

[Immunologic analysis of the pathology developing in mice as a results of intrauterine infection with the influenza virus]. / Immunologicheskii analiz patologii, razvivaiushcheisia u myshei v rezul'tate vnutriutrobongo zarazheniia virusom grippa.

The progency of C57BL/6 mice consisting of three groups: with signs of slow influenza infection ("dwarf"), "nude-like" resembling nude mice, and "nude-like" with spontaneous fur growth, was examined. The slow influenza infection in "dwarf" mice was found to be characterized by marked immunosuppression manifested by a sharp reduction of the number of antibody- and rosette-forming cells and blasttransformation of spleen lymphocytes into T- and B-mitogens. The most marked immuno-suppression was found in the "dwarfs" born to the females infected with the virus enriched with standard virions. "Nude-like" animals also had marked immunosuppression (particularly with regard to the rosette-formation), however, the "dwarfs" appeared to have more marked affection of B-cells as compared with "nude-like" mice. Gradual restoration of fur in a portion of "nude-like" animals (spontaneous growth) was due to sharp stimulation of immune responsiveness in them as manifested by a two-fold (as compared with the controls) increase in the number of antibody- and rosette-forming cells and normalization of spleen cell response to T- and B-mitogens. Differences between nude and "nude-like" mice consisting in the latter in the affection of not only T- but also B-link of immunity are discussed.

[Slow influenzal infection developing in the progeny of mice as a result of infection of the females during pregnancy]. / Medlennaia grippoznaia infektsiia, razvivaiushchaiasia u potomstva myshei v rezul'tate zarazhenii samok v period beremennosti.

Transplacental transmission of influenza virus from female mice infected during pregnancy may be detected as early as one day after virus inoculation, and the concentration of the infectious virus in fetal tissues is proportional to the infective dose. The intrauterine infection of fetuses leads to the development in a portion of progeny of slow influenza infection the frequency of which depends on the size of the dose used for inoculation of pregnant females. The slow influenza infection developed with similar effectiveness in the progeny of SHK colony mice and C57BL/6 line. As a result of influenza virus infection of pregnant C57BL/6 mice, there were specimens among their progeny devoid of body fur resembling the line of athymic nude mice. It is suggested that the birth of such nude mice is due to reversible changes in the thymus occurring under the influence of influenza virus.

[Experimental slow influenza infection in mice]. / Eksperimental'naia medlennaia grippoznaia infektsiia u myshei.

In baby mice born to mothers--virus carriers (surviving for various periods after intranasal administration of influenza virus), infectious persisting influenza virus in titres of 10(0.5) to 10(2.5) EID50/0.1 ml was found in the blood, lungs, livers, kidneys, spleens, and brains. Not infrequently, such animals developed a severe pathological process accompanied by growth retardation and characterized by progressive involvement of the hypothalamus, immunocompetent organs, endocrine system and always terminating by the death of the animals. Possible mechanisms of the described slow form of influenza infection are discussed.