VOL. 33 S-5 CHEMO THERAPY Fig. 1 Chemical structure of HAPA-B 1-N-[ (2 S)-3-Amino-2-hydroxypropiony1]-4- O-(6-amino-6 - deoxy-ƒ -D- glucopyranosyl) -6

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Transcription:

VOL. 33 S-5 CHEMO THERAPY Fig. 1 Chemical structure of HAPA-B 1-N-[ (2 S)-3-Amino-2-hydroxypropiony1]-4- O-(6-amino-6 - deoxy-ƒ -D- glucopyranosyl) -6- O-[3-deoxy-4 -C-methyl-3 -(methylamino) -ƒà-l- arabinopyranosyl]-2 -deoxystreptamine

CHEMO THERAPY NOV, 1985 Table 1 Antibacterial spectrum Gram positive and negative aerobic bacteria MIC (Đg/ml) 106 cfu/ml

VOL. 33 S-5 CHEMO THERAPY Table 2 Antibacterial spectrum Gram positive and negative anaerobic bacteria MIC (Đg/ml)106 cfu/ml

CHEM OTHERAPY NOV. 1985 Fig. 2 Susceptibility of S. aureus (54 strains) Fig. 3 Susceptibility of S. epidermidis (19 strains) Fig. 4 Susceptibility of E. coli (143 strains) Fig. 5 Susceptibility of K. pneumoniae (47 strains)

VOL. 33 S-5 CHEM OTHERAPY Fig. 6 Susceptibility of C. freundii (28 strains) Fig. 7 Susceptibility of E. cloacae (13 strains) Fig. 8 Susceptibility of P. mirabilis (37 strains) Fig. 9 Susceptibility of P. vulgaris (26 strains)

CHEMOTHERAPY NOV. 1985 Fig. 10 Susceptibility of P.rettgeri (12 strains) Fig. 11 Susceptibility of P.morganii (33 strains) Fig. 12 Susceptibility of S. marcescens (79 strains) Fig. 13 Susceptibility of P.aeruginosa (109 strains)

VOL.33 S-5 CHEMOTHERAPY Fig. 14 Susceptibility of GMr S. marcescens (41 strains) Fig. 15 Susceptibility of GM' P. aeruginosa (30 strains) Fig. 16 Comparison of MICR) and MICgo against clinical isolates S. aureus (54) S. epidermidis (19) E. coli (143) K. pneumoniae (47) C. freundii (28) E. cloacae (13) P. mirabilis (37) P. vulgaris (26) P. rettgeri (12) P. morganii (33) S. marcescens (79) P. aeruginosa (109) GMr S. marcescens (41) GM P. aeruginosa (30)

CHEMOTHERAPY NOV. 1985 Fig. 17 Resistance patterns of S. marcescens (76 strains) Fig. 18 Resistance patterns of P. aeruginosa (39 strains)

VOL. 33 S-5 CHEMOTHERAPY

CHEMOTHERAPY

CHEMOTHERAPY

CHEMOTHERAPY Fig. 21 Bactericidal activity of HAPA-B, AMK and GM against mixed incubation with E. coli and S. marcescens

CHEMOTHERAPY Table 3 Effect of inoculum size, ph, horse serum and medium on the MIC of HAPA-B * : MH: Mueller Hinton Medium NA: Nutrient Agar HIA: Heart Infusion Agar BHIA: Brain Heart Infusion Agar ABM3: Antibiotic Medium 3 N. G.: Control not growth Table 4 Effect of antibiotics on poly U dependent polypeptide synthesis in cell extract obtained from E. coli Q-13 The reaction mixture contained, in 200 ƒê1: 10 mm, Tris-HCl buffer ph 7.8; 16 mm, Mg(OAc)2: 50 mm, NH4Cl; 0.1 mm, DTT: 1.0mM, ATP; 0.05 mm, GTP: 5 mm, PEP: 40 ƒêg, PEP Kinase: 20 ƒêg, poly U: 0.25 ƒêci, 14C-aminoacid; 20 ƒêg, trna; R-100, 15 A260 units: S-100, 400 ƒêg. The incubations was for 20 miniutes at 37 Ž and the reaction was for labeled amino acid incorporated into TCA-insoluble material was counted in a Aloca Scintillation Spectrometer.

CHEMOTHERAPY Nov 1985 Table 5 In vivo antibacterial activities of HAPA-B, AMK and GM on systemic infections in mice Mice: Sic: ICR strain, male, 4 weeks old, 10 animals/group. Challenge: i. p., 5% mucin suspension. Administration : i. m., 1 hr. after infection. ED50 : 7 days after challenge. Van der Waerden method. * : 95% confidence limit

CHEMOTHERAPY Table 6 Protective effect of HAPA-B, AMK and GM against experimental mixed infection with E. coli and S. marcescens in mice Mice: Slc: ICR strain, male, 4 weeks old, 8 animals/group. Challenge: i. p., 5% mucin suspension. Administration: i. m., 1 hr after challenge. Bacterial detected: heart blood of dying mice, E. coli alone, S. marcescens alone and the said both. Table 7 Protective effect of HAPA-B on respiratory infections in mice Mice: Slc: ICR strain, male, 4 weeks old, 10 animals/group. b): cyclophosphamide treatment (4 mg/ mouse, i. p.) for 4 days before infection. Challenge: Aerosol infection apparatus used for CIS inhalation chamber apparatus (CLEA JAPAN INC.). Administration: i. m., a): 2,5 and 8 hrs. after infection, b): 1 and 4 hrs. after infection.

CHEMOTHERiAPV Fig. 22 Therapeutic effect of HAPA-B, AMK and GM against experimental urinary tract infection with P. aeruginosa in mice Mice: Sic: ICR strain, femal, 5 weeks old, 5 animals/group. Challenge: Transurethrally inoculated, P. aeruginosa 0844 5 ~105 cfu/0.05 ml Administration. i. m., 24 hrs. after challenge from twice daily for 5 days. Bacterial recovery: kidneys, 6 days after challenge. hydoroxybutyryl)-gentamicin B and 1-N-(S-3-3) MILLER, G. H.; P. J. S. CHIU & J. A. WAITZ: 2) NAGABHUSHAN, T. I.; A. B. COOPER, H. TASAI, P. J. L. DANIELS & G. H. MILLER: The syntheses and biological properties of 1-N-(S-4-amino-2- amino-2-hydoroxypropionyl) gentamicin B. J. Antibiotics 31: 681 `687, 1978 Biological activity of SCH 2140, the 1-N-S-ahydoroxy-ƒÀ- aminopropionyl derivative of gentamicin B. J. Antibiotics 31: 688 `696, 1978 4) GOERING, R. V.; C. C. SANDERS & W. E. SANDERS: In vivo analysis of structure-activity relationships among four aminoglycosides: gentamicin, netii-

CHEMOTHERAPY Fig. 23 Plasma levels of HAPA-B and AMK in mice micin, 1-N-HAPA gentamicin B and amikacin. Curr. Ther. Res. 26: 329 `341, 1979 7) NIRENBERG, M. W.: Cell free protein synthesis tract infection with Pseudomonas aeruginosa in mice. Infect. Immun. 22: 508 `515, 1978 Chemotherapy 30: 1237 `1249, 1982 11) MOROHOSHI, T.; M. TORIYA, S. YOKOIYAMA, K. FUJIMOTO, K. HAYANO, S. GOTO & A. Tsuji: The acetylation of 6'-amino group of amikacin by a directed by messenger RNA."Method in Enzymology" ed. by S. P.Colowick & N. O. Kaplan, Academic Press Inc., New York, vol.vi, pp 17 `23, 1963 9) NISHI, T. & K. TUSHUCHIYA: Experimental urinary new enzyme prepared from Serratia sp.. J. Antibiotics 37: 1687 `1691, 1984

CHEMOTHERAPY IN VITRO AND IN VIVO ANTIBACTERIAL ACTIVITY OF HAPA-B, A NEW AMINOGLYCOSIDE ANTIBIOTIC SHIGEYUKI YOKOIYAMA, MINORU TORIYA, TOSHIRO MOROHOSHI, YOSHINORI SIRITANI, AKIKO TAKASHIMA and KAZUO HAYANO Research Laboratories, Toyo Jozo Co., Ltd., SACHIKO GOTO and AKIYOSHI TSUJI Department of Microbiology, School of Medicine, Toho University The in vitro and in vivo antibacterial activities of HAPA-B, a new aminoglycoside, were investigated in comparison with those of amikacin, gentamicin, dibekacin and tobramycin. The follwing results were obtained. HAPA-B showed a broad antibacterial spectrum against both gram-positive and gram-negative bacteria. Among them, S. marcescens, C. freundii and E. cloacae were extremely susceptible. HAPA-B was active against most of aminoglycoside-resistant bacterial strains. It acted bactericidally and the activity war stronger than that of amikacin. On the protective effects in experimental infections with various bacteria, HAPA-B showed excellent therapeutic effects as obtained in in vitro. Furthermore, HAPA-B was effective in experimental infections caused by various aminoglycoside-resistant bacteria including amikacinresistant strains. The peak value of the serum level of HAPA-B in mice gave almost same features as that of amikacin.

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