The Journal of Antibiotics

CHICAMYCIN, A NEW ANTITUMOR ANTIBIOTIC

I. PRODUCTION, ISOLATION AND PROPERTIES

MASATAKA KONISHI, MASAMI HATORI, KOJI TOMITA, MASARU SUGAWARA, CHIHARU ...

1984 Volume 37 Issue 3 Pages 191-199
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.191

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Chicamycin is a new antitumor antibiotic produced by a strain of Streptomyces albus, No. J576-99. The antibiotic is extractable into organic solvents from the fermentation broth and is obtained in two active forms, chicamycins A and B, depending upon the isolation procedure used. Chicamycin A is not a natural antibiotic but the methanol adduct of naturally produced chicamycin B. Both forms of the antibiotic have weak antibacterial activity against some Gram-positive and acid-fast bacteria. They inhibit the growth of experimental tumors such as P388 mouse leukemia.

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CHICAMYCIN, A NEW ANTITUMOR ANTIBIOTIC

II. STRUCTURE DETERMINATION OF CHICAMYCINS A AND B

MASATAKA KONISHI, HIROAKI OHKUMA, NOBUAKI NARUSE, HIROSHI KAWAGUCHI

1984 Volume 37 Issue 3 Pages 200-206
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.200

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Structures of chicamycins A and B have been determined from a series of chemical degradation studies coupled with spectroscopic analysis. Chicamycin A is 2(S), 11(R), 11a(S)-1, 2, 3, 10, 11, 11a-hexahydro-2, 8-dihydroxy-7, 11-dimethoxy-5H-pyrrolo-[2, 1-c][1, 4]-benzodiazepin-5-one, and chicamycin B is 2(S), 11a(S)-1, 2, 3, 11a-tetrahydro-2, 8-dihydroxy-7-methoxy-5H-pyrrolo-[2, 1-c][1, 4]-benzodiazepin-5-one which is the demethanol form of chicamycin A. The structure of chicamycin B is closely related to that of neothramycin, differing only in the position of a hydroxyl substituent on the pyrrolidine ring.

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[R-(Z)]-4-AMINO-3-CHLORO-2-PENTENEDIOIC ACID, A NEW ANTIBIOTIC

FERMENTATION, ISOLATION AND CHARACTERIZATION

LOUIS CHAIET, BYRON H. ARISON, RICHARD L. MONAGHAN, JAMES P. SPRINGER, ...

1984 Volume 37 Issue 3 Pages 207-210
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.207

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A new unsaturated glutamic acid analog, 4-amino-3-chloro-2-pentenedioic acid (ACPA) was isolated from a fermentation broth produced by a strain of Streptomyces. ACPA has a very narrow antibacterial spectrum, which is virtually limited to Micrococcus luteus.

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STRUCTURES OF OA-6129D AND E, NEW CARBAPENAM ANTIBIOTICS

TAKEO YOSHIOKA, AZUMA WATANABE, IKUO KOJIMA, YASUTAKA SHIMAUCHI, MITSU ...

1984 Volume 37 Issue 3 Pages 211-217
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.211

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The structures and stereochemistry of OA-6129D and E, new carbapenam compounds produced by Streptomyces sp. OA-6129, were determined by spectroscopic analysis and chemical transformation.

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STRUCTURE-ACTIVITY RELATIONS OF 5, 6-cis CARBAPENEM ANTIBIOTICS AND ROLE OF FACTORS DETERMINING SUSCEPTIBILITY OF ESCHERICHIA COLI TO β-LACTAM ANTIBIOTICS

YUKIMASA NOZAKI, SETSUO HARADA, KAZUAKI KITANO, AKIRA IMADA

1984 Volume 37 Issue 3 Pages 218-226
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.218

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The antibacterial activities of twelve 5, 6-cis carbapenem antibiotics, including four semisynthetic derivatives of C-19393 H₂ and S₂, against 15 microorganisms were examined, and their structure-activity relations are discussed in relation to minimum inhibitory concentrations against Staphylococcus aureus and Escherichia coli as a Gram-positive and a Gram-negative standard strain, respectively. The contribution of chromosomal β-lactamase (amp C), permeability barrier, and penicillin-binding protein (PBP) 1B to the resistance of E. coli to these carbapenem antibiotics was examined using mutants lacking each of these cellular components.

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CONFORMATIONAL FLEXIBILITY OF THE METHYLTETRAZOLETHIOMETHYL SIDE CHAIN OF β-LACTAM ANTIBIOTICS

A COMPUTER GRAPHICS STUDY

DONALD B. BOYD

1984 Volume 37 Issue 3 Pages 227-234
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.227

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Analysis of X-ray crystallographic data for cephalosporins and 1-oxacephalosporins shows that, although the 1-methyl-1H-tetrazol-5-ylthiomethyl side chain at position 3 of a bicyclic β-lactam nucleus has certain conformational preferences, it also has considerable flexibility. Both the C₄=C₃-C_3'-S and C₃-C_3'-S-C_5″ torsional angles are frequently observed in the vicinity of ±90°. The distance between the tetrazole ring carbon C_5″ and the 4-carboxyl carbon ranges from 4.07 to 5.65 Â. Mean bond lengths and bond angles for the 3 and 4 side chains are tabulated.

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AN IN VITRO SCREENING METHOD FOR ANTITUMOR AND/OR ANTITUMORIGENIC SUBSTANCES INVOLVING THE TRANSFORMATION OF CHICK EMBRYO FIBROBLASTS INFECTED WITH ROUS SARCOMA VIRUS

MIEKO TAKEUCHI, YOSHIO SATO, KAZUO NITTA

1984 Volume 37 Issue 3 Pages 235-238
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.235

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An efficient in vitro screening method for antitumor and/or antitumorigenic substances was established. The method is based on determining inhibitory effect of a compound on an RSV-induced tumorigenic process and the growth of the established tumor cells in a single assay system in the presence of normal cells. These effects were determined by inhibition of focus formation in a culture of chick embryo fibroblasts, while the nonspecific cytotoxic effect was determined by inhibition of the protein content of the same culture. The efficiency of this method in screening drugs was confirmed by testing various clinical and preclinical compounds.

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SYNERGISTIC EFFECT OF PEPLOMYCIN IN COMBINATION WITH BLEOMYCIN ON L5178y MOUSE LYMPHOMA CELLS IN VIVO

W. E. G. MÜLLER, R. K. ZAHN, A. MAIDHOF, H. C. SCHRÖDER, M. ...

1984 Volume 37 Issue 3 Pages 239-243
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.239

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Studying the treatment of NMRI mice with ip injections of bleomycin (BLM) for 5 days we found an approximate LD₅₀ of 35 mg/kg; the toxicity of peplomycin (PEP) was slightly higher (LD₅₀: approximately 25 mg/kg). The effect of the two drugs on growth of L5178y mouse lymphoma cells in NMRI mice was examined. BLM alone caused at a concentration of 2.5 mg/kg an almost complete inhibition of tumor cell growth; the same effect was determined with 1 mg PEP/kg. At these concentrations the drugs caused an increase of the survival time of 110% (BLM) or 104% (PEP). Given in combination, one-sixth of the optimal doses yielded an 100% increase of the median survival time. These results indicate a significant synergistic activity of the PEP-BLM combination on L5178y cell growth in vivo (FIC index: 0.34).

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POTENTIATION OF TUMORICIDAL PROPERTIES OF MURINE MACROPHAGES BY NOCARDIA RUBRA CELL WALL SKELETON (N-CWS)

NORIAKI INAMURA, TAKASHI FUJITSU, KUNIO NAKAHARA, MICHIYO ABIKO, YOKO ...

1984 Volume 37 Issue 3 Pages 244-252
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.244

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Intraperitoneal injection of squalene-treated cell wall skeleton of Nocardia rubra (N-CWS) caused increase in number of peritoneal exudate cells (PEC). Adherent macrophages obtained from N-CWS-treated PEC suppressed growth of methylcholanthrene-induced fibrosarcoma (Meth-A), when injected intradermally with the tumor cells into BALB/c mice. The macrophages showed strong cytotoxicity against Meth-A cells in vitro. When treated with 10 μg/ml of N-CWS in vitro, proteose peptone-induced macrophages acquired tumoricidal property but resident macrophages showed no cytotoxicity after the treatment. In the supernatant of spleen cells cultured for 72 hours in the presence of N-CWS (10 μg/ml), the presence of (a) factor(s) with macrophage activating effect was observed. This factor, shown to be identical to macrophage activating factor (MAF) in molecular weight, showed synergy with N-CWS in potentiating macrophage cytotoxicity against tumor cells.

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INHIBITION OF CHITIN METABOLISM BY AVERMECTIN IN SUSCEPTIBLE ORGANISMS

PETER H. CALCOTT, RAYMOND O. FATIG, III

1984 Volume 37 Issue 3 Pages 253-259
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.253

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Avermectin inhibits Mucor miehei and Artemia salina chitin synthesis and to a degree DNA synthesis in the former. The antibiotic interferes with chitin turnover in brine shrimp and inhibits Streptomyces antibioticus chitinase activity in vitro. In light of the proposed mode of action of avermectin and the anomolies in the literature, it is proposed that avermectin can kill susceptible organisms not only by a neurotoxic mechanism but also by inhibiting chitin turnover and synthesis at low concentration and thus the molting/ecdysis process.

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INHIBITION OF DNA REPLICATION AND MEMBRANE TRANSPORT OF SOME NUTRIENTS BY CLAZAMYCIN IN ESCHERICHIA COLI

MAKOTO HORI, KYOKO NAITO, NOBUO SAKATA, YOSHIMASA UEHARA, HAMAO UMEZAW ...

1984 Volume 37 Issue 3 Pages 260-266
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.260

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Growth of Escherichia coli in a nutrient medium was inhibited by 100 μg/ml of clazamycin and at this concentration, the viable cell number decreases slowly. Elongated cells were observed in the treated cultures. The bactericidal activity was abolished by high concentrations of either sucrose or sorbitol but not by chloramphenicol. Non-growing cells suspended in a medium devoid of both carbon and nitrogen sources were killed by clazamycin more rapidly than cells in a rich medium. Incorporation of radioactive thymidine, uridine, leucine and N-acetylglucosamine into cellular macromolecules was inhibited to a similar extent. Permeability of N-acetylglucosamine and leucine was blocked by clazamycin. On the other hand, membrane transport of thymidine was only slightly inhibited. Thymidine-derived radioactivity accumulated as dTTP in the cells suggesting that DNA synthesis was blocked at the polymerization step. DNA synthesis in toluene-treated cells was also sensitive to clazamycin while the repair DNA synthesis induced by bleomycin in these cells was not. DNA-repair deficient mutants of E. coli were as sensitive to clazamycin as their DNA-repair proficient counterparts.

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A SIMPLE SYSTEM FOR STUDYING ANTIBIOTIC BINDING TO LEUKOCYTES

GARY D. GRAY, GRETA M. OHLMANN, CHARLES W. FORD, VINCENT P. MARSHALL

1984 Volume 37 Issue 3 Pages 267-274
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.267

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Studies on the interaction between antibiotics and polymorphonuclear leukocytes (PMLs) usually require the availability of radiolabeled antibiotic, that the antibiotic kill intraleukocyte pathogens, or that the antibiotic affect some function of the leukocyte. The system described here does not have the requirements above but depends instead upon anti-staphylococci activity. The key features of the system are that, following incubation, extracellular antibiotic was removed from PMLs by centrifugation, contact between Staphylococcus aureus 502A and the phagocyte-antibiotic complex was assured by centrifugation at 4°C in 96 well tissue culture dishes, phagocytosis was induced by incubation at 37°C, and assessment of surviving bacteria was accomplished by collecting [³H]thymidine labeled bacteria using a cell harvester. Antibiotics that were active in this system included naphthalenic ansamycins (rifamycins and streptovaricins), lincosaminides (clindamycins and pirlimycins), coumarins (novobiocin), erythromycin, tetracycline, tyrocidine and paulomycin.

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RELEVANCE OF IN VITRO ANTIBACTERIAL ACTIVITIES AND PHARMACOKINETIC PROPERTIES OF ANTIPSEUDOMONAL β-LACTAM ANTIBIOTICS TO THEIR THERAPEUTIC EFFECTS ON URINARY TRACT INFECTION CAUSED BY PSEUDOMONAS AERUGINOSA P 9 IN MICE

MASAFUMI NAKAO, TAKESHI NISHI, MASAHIRO KONDO, TAKESHI FUGONO, AKIRA I ...

1984 Volume 37 Issue 3 Pages 275-284
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.275

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The therapeutic effects of seven antipseudomonal β-lactam antibiotics on experimental urinary tract infection caused by Pseudomonas aeruginosa P 9 in mice were compared, and the results were analyzed in relation to their in vitro antibacterial activities and pharmacokinetic properties. The CD₅₀ values were (mg/kg): cefsulodin, 6.19; cefoperazone, 162; sulbenicillin, 167; ticarcillin, 184; azlocillin, 121; mezlocillin, 390; and piperacillin, 227. Cefsulodin was more active than the other antibiotics not only in therapeutic effects but also in in vitro antibacterial effects evaluated according to growth inhibitory, bactericidal, and bacteriolytic activities. It also penetrated and persisted well in the kidney of mice. The therapeutic effects of cefoperazone, azlocillin, and piperacillin were much less than expected from their in vitro antibacterial activities; the CD₅₀ values were more than 18-fold as large as that of cefsulodin, whereas the differences of their MIC values were less than four-fold.

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EFFECT OF INFUSION TIME ON THE PHARMACOKINETICS OF DIBEKACIN IN RABBITS

A. S. NAVARRO, J. M. LANAO, A. DOMINGUEZ-GIL

1984 Volume 37 Issue 3 Pages 285-292
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.285

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A study was made of the serum levels and of the pharmacokinetic parameters of dibekacin after administration by intravenous infusion at a dose of 2 mg/kg of the drug to rabbits using different infusion times. The peak serum level (C_max) was seen to decrease progressively on increasing infusion time. The maximum value of C_max was obtained after administration of the antibiotic by single bolus injection with an average value of 18.297±9.694μg/ml, while the minimum value was obtained after intravenous infusion over 1 hour, with an average value of 6.597±1.250μg/ml. A series of linear relationships was established between different pharmacokinetic parameters and the infusion time and a decrease was observed in the pharmacokinetic parameters α, K₁₂, K₂₁ and K₁₃ when the infusion time was increased. Changes were also observed in the distribution kinetics of dibekacin in the rabbit on varying the infusion conditions, suggesting alterations in the access and permanence of the antibiotic in tissues.

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A NOVEL CHARACTER OF ACYLAMINOBENZYLPENICILLIN APALCILLIN, IN BINDING TO PENICILLIN-BINDING PROTEINS OF ESCHERICHIA COLI AND PSEUDOMONAS AERUGINOSA

MASATOMO FUKASAWA, HIROSHI NOGUCHI, SUSUMU MITSUHASHI, FUMITOSHI ISHIN ...

1984 Volume 37 Issue 3 Pages 293-296
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.293

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SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF A MODIFIED NUCLEAR ANALOGUE OF PIPERACILLIN

MICHAEL J. DRIVER, PETER H. BENTLEY, RONALD A. DIXON, ROBERT A. EDMOND ...

1984 Volume 37 Issue 3 Pages 297-299
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.297

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A TOTAL SYNTHESIS OF CHICAMYCIN A

A NEW PYRROLO[1, 4]BENZODIAZEPINE ANTITUMOR AGENT

T. KANEKO, H. WONG, T. W. DOYLE

1984 Volume 37 Issue 3 Pages 300-302
Published: 1984
Released on J-STAGE: April 19, 2006

DOIhttps://doi.org/10.7164/antibiotics.37.300

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