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Biomedical subjects

K Okonogi

Publications and source records attributed to K Okonogi.

At least 55 records · Page 3Linked to original sources
PubMed1990

Activation of the cAMP cascade inhibits an early event involved in murine macrophage Ia expression.

The ability of interferon-gamma (IFN gamma) to increase class II major histocompatibility complex (class II MHC) gene products in murine macrophages involves activation of Na+/H+ exchange (Prpic V., Yu, S. F., Figueiredo, F., Hollenbach, P. W., Gawdi, G., Herman, B., Uhing, R. J., and Adams, D. O. (1989) Science 244, 469-471). The ability of IFN gamma to increase class II MHC gene product expression is inhibited by a variety of agents. In the present studies, the involvement of cAMP-dependent protein kinase in modulating IFN gamma-induced expression of MHC gene products and the mechanism of regulation were assessed in macrophages treated with agents which activated cAMP-dependent protein kinase by different molecular mechanisms. Prostaglandin E2 (PGE2) produced a rapid (within 30 s) dose-dependent elevation of cAMP which was paralleled by the activation of cAMP-dependent protein kinase. The elevation of cAMP by PGE2 was still evident at 1 h and maintained through a 4-h incubation. Concentrations of PGE2 which activated the protein kinase produced a dose-dependent inhibition of surface expression of I-A and transcription of class II MHC genes. Inhibition of IFN gamma-induced class II MHC gene product expression was also observed in macrophages treated with agents which activated cAMP-dependent protein kinase by postreceptor mechanisms. Dibutyryl-cAMP (0.01-1 mM), 25 microM forskolin, 0.1 micrograms/ml cholera toxin, and 3-isobutyl-1-methylxanthine (0.1-1 mM) each suppressed IFN gamma-induced cell surface I-A expression, class II MHC gene transcription, and 22Na+ influx. The results are consistent with the suggestion that activation of cAMP-dependent protein kinase regulates an early transductional event initiated by IFN gamma, perhaps Na+/H+ exchange, which is involved in regulating transcription of class II MHC genes and their subsequent expression.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Examination of relative rates of cAMP synthesis and degradation in crude membranes of adipocytes treated with hormones.

The impact of changes in the activation state of the low Km cAMP phosphodiesterase (PDE) on cAMP output in adipocyte membranes was assessed by measuring the product of cAMP synthesis and degradation in the membrane preparation simultaneously. Crude membranes were prepared from adipocytes treated with the cAMP analog, 8-pCl phi S-cAMP and from adipocytes treated with 2 nM insulin. Using membranes from control and treated cells, adenylate cyclase was activated with various concentrations of forskolin and cAMP production (synthesis minus degradation) was measured with and without complete PDE inhibition using the specific inhibitor CI-914. Half maximal inhibition of the low Km cAMP PDEs in control membranes was produced by 1.16 +/- 0.07 microM CI-914 and greater than 98% of the activity was inhibited by 100 microM CI-914. The I50 and the concentration of CI-914 producing complete PDE inhibition in membranes from 8-pCl phi S-cAMP or insulin-treated cells were identical to those seen in membranes from control cells. Treatment of adipocytes with 8-pCl phi S-cAMP or with insulin did not modify basal rates of cAMP synthesis or alter the ability of adenylate cyclase to be activated by forskolin. The impact of PDE activity on cAMP accumulation was relatively small in membranes from control cells, but treatment of adipocytes with 8-pCl phi S-cAMP or with insulin activated the low Km cAMP PDE and caused a marked decrease in cAMP accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1990

[Mechanism of beta-lactam-resistance in methicillin-resistant Staphylococcus aureus].

The role of penicillin-binding protein (PBP) 2' in the expression of beta-lactam-resistance was investigated using methicillin-resistant Staphylococcus aureus (MRSA) strains with different level of resistance. Both high- and moderate-level MRSA produced very similar PBP 2' with low affinities for beta-lactam antibiotics. Affinities of antibiotics for PBP 2' (I50, concentration which inhibits [14C] benzylpenicillin-binding by 50%) correlated well with their antibacterial activities (MIC) in a high-level MRSA, but did not in a moderate-level MRSA. High-level MRSA contained a larger amount of PBP 2' than moderate-level MRSA, and the amount of PBP 2' decreased by increasing the temperature of the culture; the extent of decrease was larger in a strain which was sensitive at 37 degrees C than a strain which exerted relatively high level resistance even at 40 degrees C. A cephamycin-resistant, methicillin-sensitive strain began to synthesize PBP 2' by adding cephamycin-type antibiotics to the medium and consequently acquired resistance to methicillin. Latent MRSA producing no PBP 2' generated clones which produced PBP 2' constitutively and were highly resistant to all beta-lactams. These results suggest that the presence of PBP 2' is critical for the expression of beta-lactam-resistance in MRSA and the degree of the resistance depends mainly on the amount of PBP 2' which differs from strain to strain and is influenced by environments such as temperature and the presence of inducer.

Anti-Bacterial Agents↗
PubMed1989

Emergence of methicillin-resistant clones from cephamycin-resistant Staphylococcus aureus.

Staphylococcus aureus strains specifically resistant to cephamycin antibiotics have been found among recent clinical isolates. These strains formed penicillin-binding protein (PBP) 2' and became phenotypically resistant to methicillin after induction with cefoxitin. Other cephamycin-type antibiotics also induced methicillin-resistance, whereas non-cephamycin-type cephalosporins such as cefmenoxime and ceftizoxime did not do so. The clones that constitutively synthesized PBP 2' arose from the cephamycin-resistant strains at a frequency of 10(-5). They were indistinguishable from clinically isolated methicillin-resistant S. aureus (MRSA). Cephamycin-resistant S. aureus may be a source for emerging MRSA.

Bacterial Proteins↗
PubMed1986

Induction of beta-lactamase in Proteus vulgaris.

Various beta-lactam antibiotics, including monocyclic beta-lactams, induced the beta-lactamase of Proteus vulgaris; when clinical isolates were induced by benzylpenicillin, each strain produced a single beta-lactamase but the activity per milligram dry weight differed from strain to strain. The beta-lactamases of the P. vulgaris strains were heterogeneous with respect to their isoelectric points, but had almost the same specific activities, substrate specificities and Michaelis constants. The kinetics of beta-lactamase formation were investigated in three strains, each with a different beta-lactamase activity. Differential rates of enzyme synthesis and peak activity depended on the concentration of inducer. The plots of the reciprocals of the differential rates versus the reciprocals of the inducer concentrations were linear, and the maximum rate of enzyme synthesis and the concentration of the inducer giving half-maximum induction were determined from this double reciprocal plot. The maximum rates of enzyme synthesis were different in the three strains. The kinetic analysis of beta-lactamase formation revealed that the beta-lactamase activities in a single bacterial species were determined by differences in the rate of enzyme synthesis and not by differences in the properties of the enzyme.

Cephalosporins↗
PubMed1985

Effect of beta-lactamase induction on susceptibility to cephalosporins in Enterobacter cloacae and Serratia marcescens.

For Enterobacter cloacae GN5797 and Serratia marcescens 72-2, which produce inducible beta-lactamases and respond antagonistically to many combinations of cephalosporins, the changes in beta-lactamase activity and sensitivity to cephalosporins were examined during semi-continuous cultivation in which the concentration of inducers was decreased by two-fold dilution of the culture every 30 min starting from 1 h after the addition of inducers. The levels of beta-lactamase, which peaked at 0.5-2 h after induction, decreased concomitantly with the disappearance of the inducers in the culture, and returned to the uninduced levels by 6 h. The ability of cefoxitin and cefmetazole to induce beta-lactamases was more potent than that of cefazolin and cefotiam. The sensitivity to some cephalosporins, judged by the MIC and bactericidal effect, was slightly decreased at an early stage of induction, and reverted to the uninduced levels within several hours after the inducers were depleted.

Cephalosporins↗
PubMed1985

In vitro and in vivo antibacterial activities of carumonam (AMA-1080), a new N-sulfonated monocyclic beta-lactam antibiotic.

The in vitro and in vivo antibacterial activities of carumonam (AMA-1080), a synthetic sulfazecin derivative, were compared with those of aztreonam, cefoperazone, ceftazidime, and cefsulodin. Carumonam was highly active in vitro against members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Haemophilus influenzae and weakly active against Streptococcus pneumoniae, but it was not active against Staphylococcus aureus. The MICs of carumonam for 90% of 1,156 clinical Enterobacteriaceae isolates were between 0.013 and 25 micrograms/ml, which were the lowest MICs of the antibiotics tested. The MIC of carumonam for 90% of Klebsiella oxytoca was 0.2 micrograms/ml, whereas that of aztreonam was 50 micrograms/ml. The superiority of carumonam to aztreonam and the reference cephalosporins was also demonstrated by their activities against Klebsiella pneumoniae and Enterobacter cloacae. The MIC of carumonam for 90% of P. aeruginosa was 12.5 micrograms/ml, which was comparable to the MICs of aztreonam and ceftazidime. Carumonam showed a high affinity for the penicillin-binding protein 3 of gram-negative bacteria, but not for the penicillin-binding proteins of S. aureus and Bacteroides fragilis. Carumonam was resistant to hydrolysis by 12 plasmid-mediated beta-lactamases and 7 chromosomal beta-lactamases. It was more stable than aztreonam to hydrolysis by the beta-lactamase of K. oxytoca; this stability is related to the superiority of the in vitro and in vivo activities of carumonam to those of aztreonam against this species. In general, the protective activities (50% effective dose) of carumonam and reference antibiotics in mice with experimental intraperitoneal infections correlated with the in vitro activities (MIC); carumonam showed excellent protective activity against most aerobic gram-negative bacteria.

Animals↗
PubMed1985

Formadicins, new monocyclic beta-lactam antibiotics of bacterial origin. I. Taxonomy, fermentation and biological activities.

A Gram-negative bacterium produces new monocyclic beta-lactam antibiotics with a formylamino substituent, named formadicins A, B, C and D. The producing bacterium was taxonomically characterized and designated as Flexibacter alginoliquefaciens sp. nov. YK-49. Formadicins have narrow antibacterial spectra. They are highly active against some species of Pseudomonas, Proteus and Alcaligenes. Of the four, formadicin C shows the most potent antibacterial activity. Several amino acids such as glycine, D-alanine and D-leucine were antagonistic against formadicins. Formadicins, especially formadicins A and C having the formylamino substituent bound to the 3-position of a beta-lactam nucleus, were highly resistant to hydrolysis by various types of beta-lactamases. Formadicins A and C showed affinity for penicillin-binding proteins (PBPs) 1A and 1B in Pseudomonas aeruginosa IFO 3080, but formadicin B and nocardicin A showed affinity only for PBP 1B. Formadicins A and C did not lyse Escherichia coli LD-2 solely at their MICs, but when combined with mecillinam each induced a rapid lysis of this organism.

Amino Acids↗
PubMed1985

Interactions of formylamino- and methoxy-substituted beta-lactam antibiotics with beta-lactamases.

Cephem and nocardicin-type monocyclic beta-lactam antibiotics with a formylamino substituent were highly resistant to hydrolysis by both penicillinases and cephalosporinases. Among antibiotics with a methoxy substituent, an N-sulfonated monocyclic beta-lactam antibiotic, sulfazecin was resistant to beta-lactamases, but cephem antibiotics were sensitive to the cephalosporinase of Enterobacter cloacae. The resistance of the antibiotics to the beta-lactamases depended primarily on the presence of the substituent, but affinity for the beta-lactamases was affected not only by the substituent but also by the presence of other side chains. Formylamino compounds and sulfazecin were as good inducers of beta-lactamases as semisynthetic 7-methoxycephalosporins, but naturally occurring 7-methoxycephalosporins were poor inducers. The inducer activities of the antibiotics were not necessarily related to their beta-lactamase stabilities. The stabilities of the compounds to the beta-lactamases were well reflected in their antibacterial activities against beta-lactamase producing bacteria.

Anti-Bacterial Agents↗
PubMed1984

Cephabacins, new cephem antibiotics of bacterial origin. IV. Antibacterial activities, stability to beta-lactamases and mode of action.

Cephabacin F group antibiotics with a 7-formylamino substituent showed antibacterial activity against a wide variety of bacteria including beta-lactamase-producing clinical isolates and anaerobic bacteria. Cephabacin H group antibiotics without the substituent showed more potent activity against Gram-positive bacteria than cephabacin F group antibiotics, but were not active against Gram-negative bacteria producing beta-lactamases. Cephabacin F group antibiotics were highly resistant to hydrolysis by various types of beta-lactamases and showed strong inhibitory activity against a cephalosporinase of Proteus vulgalis GN 4413 due to the 7-formylamino substituent. Mode of action of cephabacin F1 and H1 was examined using Escherichia coli and Bacillus subtilis as the test organisms. They showed strong lytic activity against these organisms and inhibited their peptidoglycan synthesis. Cephabacin F1 had the highest affinity for penicillin-binding protein (PBP) 1 in E. coli and PBP 4 in B. subtilis. Cephabacins showed a protective effect in experimentally infected mice.

Bacteria↗
PubMed1983

Synthesis and biological activities of the Z isomers of carbapenem antibiotics.

Naturally occurring carbapenem antibiotics having a double bond in the side chain, when refluxed in chloroform containing quarternary alkylammonium halides, were converted into Z isomers in high yields. The mechanism of this new equilibration involves intramolecular proton transfer from the carboxylic acid to the carbon alpha to the sulfur atom in the side chain as shown by deuterium-labeling experiments. Some Z isomers showed stronger protective effects in mice infected by Escherichia coli O-111 and more potent synergistic activities with cefotiam in mice infected by Proteus vulgaris GN4815 than did the naturally occurring E isomers. The decomposition rates of the Z isomers in mouse kidney homogenates were about 3-fold slower than those of the E isomers.

Animals↗
PubMed1983

Synthesis and biological activities of the Z isomers of carbapenem antibiotics.

Naturally occurring carbapenem antibiotics having a double bond in the side chain, when refluxed in chloroform containing quarternary alkylammonium halides, were converted into Z isomers in high yields. The mechanism of this new equilibration involves intramolecular proton transfer from the carboxylic acid to the carbon alpha to the sulfur atom in the side chain as shown by deuterium-labeling experiments. Some Z isomers showed stronger protective effects in mice infected by Escherichia coli O-111 and more potent synergistic activities with cefotiam in mice infected by Proteus vulgaris GN4815 than did the naturally occurring E isomers. The decomposition rates of the Z isomers in mouse kidney homogenates were about 3-fold slower than those of the E isomers.

Animals↗
PubMed1983

Synthesis and structure-activity relationships of carbapenems related to C-19393 H2.

By applying the synthetic process reported in our previous paper, we synthesized new carbapenems having various (substituted) thio and alkoxy groups at the C(3) position and 1-hydroxy-1-methylethyl and analogous groups at the C(6) position with cis- and trans-stereochemistry; the in vitro antibacterial and beta-lactamase inhibitory activities of these new carbapenems were examined. Compared to C-19393 H2, some of these compounds (e.g., 11A-a-3 approximately 5) showed improved in vitro antibacterial activity especially against Pseudomonas aeruginosa; they showed a strong beta-lactamase inhibitory activity as well. Two noteworthy effects of substituent variation at the C(6) position on the activities were observed: 1) the trans-configuration caused a definite loss; and 2) introduction of 1-hydroxycyclobutyl and 1-hydroxy-1-methylpropyl groups in place of the 1-hydroxy-1-methylethyl group caused a diminution. The carbapenem (13A-a-2) with an alkoxy group at the C(3) position had a marked decrease in activity compared to the corresponding thio-substituted carbapenem (11A-a-12).

Indicators and Reagents↗
PubMed1982

Beta-lactamase inhibitory activities and synergistic effects of 5,6-cis-carbapenem antibiotics.

Twelve 5,6-cis-carbapenem antibiotics were examined for their beta-lactamase inhibitory activities, their types of inhibitions, and their synergistic activities with other beta-lactam antibiotics. All the carbapenems inhibited eight types of beta-lactamases including cephalosporinases which were insensitive to clavulanic acid and sulbactam. The sulfonyloxy ethyl carbapenems were the most active inhibitors; they inhibited all beta-lactamases in a progressive fashion, whereas some of the hydroxyl compounds exerted non-progressive inhibition against several beta-lactamases such as those of Escherichia coli TN713 and Proteus vulgaris GN4413. Several carbapenems were inactivated by the beta-lactamases of Citrobacter freundii GN1706, P. vulgaris GN4413, E. coli TN713, and Klebsiella pneumoniae TN1698. Most of the carbapenems potentiated the antibacterial activities of ampicillin and cefotiam against beta-lactamase-producing bacteria.

Anti-Bacterial Agents↗
PubMed1981

Beta-lactamase stability and antibacterial activity of cefmenoxime (SCE-1365), a novel cephalosporin.

Cefmenoxime, a new cephalosporin antibiotic, has been shown to be stable to a Staphylococcus aureus penicillinase and R plasmid-mediated type I and type IV penicillinases. It was also resistant to hydrolysis by most cephalosporinases, but was susceptible to hydrolysis by a Proteus vulgaris beta-lactamase. Cefmenoxime was active against cephaloridine-resistant species, except Pseudomonas aeruginosa, which was moderately resistant to cefmenoxime. Cefmenoxime was an inducer of P. vulgaris beta-lactamase biosynthesis, but 1 microgram or more of the drug per ml, which inhibits most of the clinical isolates of P. vulgaris, was required for the production of detectable amounts of the enzyme. Cefmenoxime was a strong competitive inhibitor of beta-lactamases of Enterobacter cloacae, Citrobacter freundii, P. aeruginosa, and Serratia marcescens, but it did not inhibit penicillinases in spite of its resistance to hydrolysis.

Anti-Bacterial Agents↗