Biomedical subjects
Publications and source records attributed to K Kiyoshima.
4''-O-Acyl-, 4''-O-alkyl- and 4''-deoxy-tylosin derivatives were synthesized using 2'-O-acetyl-3'',4''-O-(dibutyl-stannio)tylosin as a synthetic intermediate. The in vitro biological evaluation showed that the new derivatives were active against macrolide-resistant clinical isolates of bacteria and mycoplasmas, and that they were resistant to hepatic esterase.
Essential roles for both the 23-O-mycinosyl and 4''-O-acyl moieties of 4''-O-acyltylosin derivatives in the expression of antimicrobial activity against multiple macrolide-resistant strains of Staphylococci and mycoplasmas were demonstrated by in vitro comparison of the MICs of erythromycin, josamycin, tylosin and its 3- and 4''-O-acyl derivatives, demycinosyltylosin (DMT) and its 3- and 4''-O-acyl derivatives and 23-modified 3-O-acetyl-4''-O-isovaleryl-DMT derivatives.
Eleven 4''-O-acyltylosin derivatives were synthesized and subjected to a two-step screening system consisting of antimicrobial activity and esterase stability assays. The new derivatives were all active against macrolide-resistant Staphylococci and mycoplasmas, but only 4''-O-(4-methoxy)phenylacetyltylosin and 4''-O-(4-acetyl)phenylacetyltylosin showed better resistance to mouse liver esterase than 4''-O-phenylacetyltylosin (reference compound C).
2'''-Demethoxytylosin (component IIIc), 2'''-demethoxy-4'''-epi-tylosin (component IIId) and 2'''-O-demethyltylosin (component Vb) were produced by blocked mutant strains of Streptomyces fradiae. Fermentation, isolation, structure determination and biosynthetic considerations of these tylosin analogs are described.
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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 microgram/ml against Staphylococcus aureus MS-8710. MIC values of tylosin, erythromycin and josamycin against this strain were 800 microgram/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 microgram/ml. These derivatives had also an improved antimycoplasmal activity; MIC values were 0.08 microgram/ml against macrolide-resistant strains of Mycoplasma gallisepticum. MIC values of tylosin against these strains were from 2.5 to 10 microgram/ml. Introduction of the groups described above into the 4"-OH was confirmed to increase the uptake by a resistant strain.
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Various blocked mutants were isolated from Streptomyces coeruleorubidus ME130-A4 by NTG and UV treatments. Among them, mutant strain 4N-140 produced new anthracycline feudomycins A and B having new aglycones in which the side chain at C-9 position of daunomycinone was ethyl and acetonyl, respectively. New aglycones feudomycinones C and D having methyl at C-9 and additional groups at C-10 of daunomycinone were also isolated from this strain.
Antibiotics PS-6 and PS-7 which are shown to be 5R,6R-3-(2-acetamido)ethylthio-6-isopropyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene- 2-carboxylic acid and 5R,6R-3-(E)-(2-acetamido) vinylthio-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid respectively, are new beta-lactam compounds isolated from fermentation broths of Streptomyces cremeus subsp. auratilis A271, S. fulvoviridis A933, S. olivaceus ATCC 31126 and S. flavogriseus NRRL 8139. Fermentation, isolation, physicochemical properties and structures of antibiotics PS-6 and PS-7 are described.
By microbial transformation of tylosin (I), the following eight new acyl derivatives were obtained: 3-acetyltylosin (II), 3-propionyltylosin (III), 4"-butyryltylosin (IV), 4"-isovaleryltylosin (V), 3-acetyl-4"-butyryltylosin (VI), 3-acetyl-4"-isovaleryltylosin (VII), 3-propionyl-4"-butyryltylosin (VIII) and 3-propionyl-4"-isovaleryltylosin (IX).
The antibacterial activity of acyl derivatives of tylosin were examined in vitro and in vivo. The 4"-acyl group in the acylated tylosins enhanced the antibacterial activity and antimycoplasmal activity against some macrolide-resistant strains. The orally administered 3-acetyl-4" -isovaleryltylosin produced a higher blood level in mice and rabbits than tylosin and a good therapeutic effect on the infection of Staphylococcus aureus Smith in mice.
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When a comprehensive health check-up is repeated for the purpose of health control, the individual clinical data should be evaluated carefully by a proper normal range, which must be specific to each subject, if early detection of disease is a goal. The Perfect Liberty Health Control System, a health plan run on a membership basis, has been giving its periodic multi-phasic health tests to all of the 24 000 + members biannually since 1970. Studies concerning health parameter dynamics have been made on the data obtained and these are important to the new challenging field of clinical laboratory examinations. Other helpful aspects of this punctually repeated AMHTS (Automated Multi-phasic Health Testing) on a lifetime membership basis are also presented, such as cancer detection accuracy, protection from unnecessary X-ray exposure during examinations and a new form of physician's examination supported by current laboratory-data preview.