Table Of ContentHandbook of
Experimental Pharmacology
Continuation of Handbuch der experimentellen Pharmakologie
Vol. 62
Editorial Board
G. V. R. Born, London· A. Farah, Rensselaer, New York
H. Herken, Berlin· A. D. Welch, Memphis, Tennessee
Advisory Board
S. Ebashi· E. G. Erdos' V. Erspamer· U. S. von Euler' W S. Feldberg
G. B. Koelle' O. Krayer· M. Rocha e Silva' J. R. Vane' P. G. Waser
Aminog lye si de
0
Antibiotics
Contributors
I.R. Hooper' Y. Ito' T. Koeda' S. Kondo· S. Mitsuhashi
T. Okuda' N. Tanaka' T. Tsuchiya' K. Umemura
H. Umezawa' S. Umezawa' M. Yokota
Editors
H. Umezawa and I. R. Hooper
Springer-Verlag Berlin Heidelberg New York 1982
Professor Dr. HAMAO UMEZAWA
Institute of Microbial Chemistry, 14-23 Kamiosaki 3-Chome,
Shinagawa-ku, Tokyo, Japan
Dr. IRVING R. HOOPER
Research Associate, Duke University Marine Laboratory,
Pivers Island, Beaufort, NY 28516jUSA
With 260 Figures
ISBN-13 :978-3-642-68581-1 e-ISBN-13: 978-3-642-68579-8
DOl: 10.1007/978-3-642-68579-8
Library of Congress Cataloging in Pnblication Data. Main entry under title: Aminoglycoside Antibiotics (Handbook
of experimental pharmacology; v.62). Bibliography: p. Includes index. 1. Aminoglycosides-Therapeutic use.
2. Antibiotics. I. Umezawa, Hamao, 1914--. II. Hooper, Irving R., 1921-. III. Series. [DNLM: 1. Aminoglycosides.
WI HA51L v. 62/QU75A518] QP905.H3 vol. 62 [RM666.A456]. 615:ls. 82-5638. ISBN-13:978-3-642-68581-1
(U.S.). [615:329]. AACR2.
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© by Springer-Verlag Berlin Heidelberg 1982
Softcover reprint of the hardcover 1st edition 1982
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Preface
The first useful antibiotic found by screening was streptomycin. The late Prof.
WAKSMAN started screening for antibacterial antibiotics in 1940 and, after finding
actinomycin in 1941, he and his collaborators discovered streptomycin in 1944.
This antibiotic made a great contribution in saving human lives from tuberculosis
and acute serious infections. About 1957, after wide usage of such antibiotics as
penicillin, streptomycin, chloramphenicol, tetracycline, and erythromycin, staphy
lococci and Gram negative organisms resistant to all or most antibiotic drugs ap
peared in hospital patients. The origin and treatment of such resistant strains be
came a major topic of investigation. At that time, kanamycin was discovered and
used in the treatment of resistant infections. It may be said that the appearance of
resistant strains stimulated a resurgence of research on new antibacterial antibiot
ics and their derivatives.
In 1965, kanamycin-resistant strains were found in hospital patients and,
undertaking the study of the mechanisms of resistance, I found that resistant
strains produce intracellular enzymes that can transfer either the terminal phos
phate of ATP or the acetate of acetyl-CoA to the 3'- hydroxyl or the 6'- amino group
of 2-deoxystreptamine~containing antibiotics. These results, reported in 1967,
made it possible to design new synthetic derivatives that would inhibit the growth
of kanamycin resistant strains of microorganisms. Thus, a new research area was
opened: the development of aminoglycosides useful in the treatment of drug-resis
tant infections.
Developments in carbohydrate chemistry have made it possible to synthesize
streptomycin, kanamycin and most other aminoglycoside antibiotics. From anoth
er ascpect, it can also be said that the successful total synthesis of these antibiotics
has made great contributions to the progress of carbohydrate chemistry. Deriva
tives of aminoglycosides are now produced on an industrial scale.
Microorganisms have an almost unlimited ability to produce novel com
pounds. Even at present, new types of aminoglycosides are being found in micro
bial culture filtrates. The reasons so many varied secondary metabolites are found
in microorganisms and the evolution and genetics of resistance are topics with
great relevance to biological and medical science. Considering the biochemical
characteristics offuture resistant strains, microbiologists and chemists are studying
new aminoglycosides and other structures that could inhibit the growth of present
and future resistant strains. Up to now, most success has been obtained with {3-
lactam and aminoglycoside antibiotics.
As described, there have been many important accomplishments in the bio
chemistry and chemistry of aminoglycosides. In order to review these studies, this
VI Preface
book was published. It is hoped that this book will contribute to the coming prog
ress in studies of chemotherapy, antibiotics, and carbohydrate chemistry.
Dr. IRVING R. HOOPER, my friend who collaborated with me on the publication
of this book, read carefully all manuscripts and corrected the English written by
authors outside of English-speaking countries. In behalf of these authors I wish to
thank Dr. HOOPER for his great effort in writing not only his manuscript but also
for his careful review of the papers. I wish also to thank all contributors for their
enthusiastic collaboration.
Tokyo HAMAO UMEZAWA
List of Contributors
Dr. IRVING R. HOOPER, Duke University Marine Laboratory, Pivers Island,
Beaufort, NC 28516/USA
Dr. YUKIO ITO, Microbial Research Laboratory, Tanabe Seiyaku Co., Ltd.,
2-2-50 Kawagishi, Toda-Shi, Saitama-ken 335, Japan
Dr. T AKEMI KOEDA, Research Laboratories, Meiji Seika Kaisha, Ltd., 760
Morooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa-ken 222, Japan
Dr. SIDNICHI KONDO, Institute of Microbial Chemistry, 14-23 Kamiosaki
3-Chome, Shinagawa-ku, Tokyo 141, Japan
Dr. SUSUMU MITSUHASID, Department of Microbiology, Laboratory of Bacterial
Resistance, School of Medicine, Gunma University, Showa-machi,
Maebashi-shi, Gunma-ken 371, Japan
Dr. TOMOHARU OKUDA, Microbial Research Laboratory, Tanabe Seiyaku Co.,
Ltd., 2-2-50 Kawagishi, Toda-shi, Saitama-ken 335, Japan
Dr. NOBUO TANAKA, Institute of Applied Microbiology, University of Tokyo,
1-1 Yayoi l-Chome, Bunkyo-ku, Tokyo 113, Japan
Dr. TSUTOMU TSUCIDYA, Institute of Bioorganic Chemistry, 1416 Ida,
Nakahara-ku, Kawasaki-shi, Kanagawa-ken 211, Japan
Dr. KOSIDRO UMEMURA, Research Laboratories, Meiji Seika Kaisha, Ltd.,
760 Morooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa-ken 222, Japan
Dr. HAMAO UMEZAWA, Institute of Microbial Chemistry, 14-23 Kamiosaki
3-Chome, Shinagawa-ku, Tokyo 141, Japan
Dr. SUMIO UMEZAWA, Institute of Bioorganic Chemistry, 1416 Ida, Nakahara-ku,
Kawasaki-shi, Kanagawa-ken 211, Japan
Dr. MASAYUKI YOKOTA, Research Laboratories, Meiji Seika Kaisha, Ltd.,
760 Morooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa-ken 222, Japan
Contents
CHAPTER I
The Naturally Occurring Aminoglycoside Antibiotics. I. R. HOOPER.
A. Introduction ................ 1
B. Aminoglycoses and Noncyclitol Aminoglycosides . 2
I. Aminoglycose Derivatives. . . . . . 2
II. Disaccharides and Pseudodisaccharides . . . 3
III. Trisaccharides . . . . . . . . . . . . . . 5
C. Aminocyclitol Aminoglycosides Containing Streptamine,
2-Deoxystreptamine, or Their Derivatives . . . . . . . 6
I. Monosubstituted Streptamine and 2-Deoxystreptamine
Aminoglycosides. . . . . . 7
I. 4- or 6-Substituted Cyclitol . . . . . . . . . . 7
2. 5-Substituted Cyclitol . . . . . . . . . . . . 10
II. Disubstituted 2-Deoxystreptamine Aminoglycosides . 12
1. 4,5-Disubstituted Cyclitol. 12
2. 4,6-Disubstituted Cyclitol. . . . . . . . . . . 14
III. I-N-Acyl Substituted Cyclitol . . . . . . . . . . 20
D. Aminoglycosides with Cyclitol Aglycones Other than Streptamine or
2-Deoxystreptamine . . 21
I. Nonbasic Cyclitol . 21
II. Monoaminocyclitol 22
III. Diaminocyclitol 24
References . . . . . . . . 27
CHAPTER 2
Total Synthesis and Chemical Modification of the Aminoglycoside Antibiotics.
S. UMEZAWA and T. TSUCffiYA. With 87 Figures
A. Introduction . . . . . . . . . . . . 37
B. Several Reactions and Methods Generally Useful for the Synthesis of
Aminoglycoside Antibiotics . . . . . . , . . . . . . . . . . . . 38
I. Simultaneous Protection of Vicinal Trans-Equatorial Amino and
Hydroxyl Groups . . . . 38
II. Selective Cyclic Acetalation . . . . . . . . . . . . . . . . . 38
x Contents
III. 1,2-cis-G1ycosy1ation of Aminosugars 39
IV. Selective Deoxygenation Reactions 39
1. 3-Deoxygenation . . . . . . 40
2. 3,4-Dideoxygenation. . . . . 41
V. Selective N-Protection via Temporary Metal Chelation of Vicinal
and Nonvicinal Amino-Hydroxy or Amino-Amino Groups 41
VI. Determination of the Configurations of Aminopyranosides and
Aminocyclitols by the Shift in Optical Rotation Due to Copper(lI)
Chelate Formation. . . . . . . . . . . . . . . . . . 42
C. Total Synthesis and Modification of Aminoglycoside Antibiotics . 43
I. Streptomycin Group . . . . . . . . . . . . . . . . . . 44
1. Total Synthesis of Streptomycin and Dihydrostreptomycin 44
2. Chemical Modification of Streptomycin and Dihydrostrepto-
myCIn . . . . . . . . . . . . . . . . . . . . . . .. 46
II. Pseudodisaccharides Containing 4-Substituted 2-Deoxystreptamine
- Paromamine, Neamine, and Related Compounds 47
1. Synthesis of Paromamine and Neamine . 47
2. Deoxygenated Derivatives 47
3. Epimerized Derivatives. . . . . . . . 48
4. Amino-Deoxy Derivatives . . . . . . 48
5. Derivatives Having a Side Chain or Longer Chain 48
6. 1-N-Acyl Derivatives. . . . . . . . . . . . . 50
7. Other Derivatives . . . . . . . . . . . . . . 51
III. Pseudotrisaccharides Containing 4,5-Disubstituted 2-Deoxy-
streptamine - Ribostamycin, Butirosins, and Related Compounds 51
1. Synthesis of Ribostamycin and Related Pseudotrisaccharides 51
2. Deoxy Derivatives. . . . . . . . . . . . . . . . . 53
3. 1-N-Acyl and 1-N-Alkyl Derivatives of 4,5-Disubstituted
Pseudotrisaccharides . . . . . . . . . . . . . . . . 53
IV. Pseudotetra- and Pseudopentasaccharides Containing 4,5-Disub
stituted 2-Deoxystreptamine - Neomycins, Paromomycins, Livido
mycins, and Related Compounds. . . . . . . . . . . . . . . 59
1. Total Synthesis of Neomycin C . . . . . . . . . . . . . . 59
2. Synthesis of Analogs of Neomycin, Paromomycin, and Livido-
micin B . . . . . . . . 59
3. Amino-Deoxy Derivatives 61
4. N-Alkyl Derivatives . . . 62
5. 1-N-Acyl Derivatives. . . 62
V. Pseudotrisaccharides Containing 4,6-Disubstituted 2-Deoxy
streptamine - Kanamycin, Tobramycin, Gentamicin, and Related
Compounds. . . . . . . . . . . . . 62
1. Kanamycins and Their Derivatives. . . . . . . . . . . . . 62
2. Gentamicins and Related Compounds . . . . . . . . . . . 75
3. Sisomicin, Its Derivatives, and Related Unsaturated Compounds 80
4. 1-N-Acylgentamicins and 1-N-Acylsisomicins 84
5. Seldomycin Modifications . . . . 85
6. Other 4,6-Disubstituted Derivatives 86
Contents XI
VI. Other Groups . . . . . . . . . . . 89
1. Kasugamycin and Its Modifications 89
2. Spectinomycin Group . . . . . . 90
3. Fortimicins, Istamycins, and Related Compounds 94
4. Sorbistins and Analogs. . . 94
5. Minosaminomycin ..... 96
6. Alpha,Alpha-Trehalosamine 97
References . . . . . . . . . . . . . 97
CHAPTER 3
Biosynthesis and Mutasynthesis of Aminoglycoside Antibiotics.
T. OKUDA and Y. ITO. With 42 Figures
A. Introduction ....... III
I. Historical Background III
II. Methodology .... 112
I. Application of Labeled Compounds 112
2. Application of Cell-Free Extracts of Mycelia or Enzymes 113
3. Application of Mutants 114
III. Plasmid Involvement . . . . . . . . . . . . . . 117
1. General Aspects . . . . . . . . . . . . . . . 117
2. Plasmid Involvement in Aminoglycoside Synthesis 118
3. Experimental Methods . . . 120
B. Biosynthesis of Major Aminoglycosides 121
I. Streptomycin and Bluensomycin 121
1. Biosynthesis of Subunits 122
2. Subunit Assembly . . . . . 131
3. Correlation with Cell Wall Biosynthesis 133
4. Plasmid Involvement . . . 134
II. Neomycin and Paromomycin . 135
1. Biosynthesis of Subunits 137
2. Subunit Assembly . . . . 140
3. Plasmid Involvement . . . 143
III. Ribostamycin, Xylostasin, and Butirosin . 145
I. Biosynthesis of Subunits. . . . . . . 146
2. Subunit Assembly . . . . . . . . . 148
3. Glucosamine Auxotroph and Butirosin Biosynthesis 152
4. Plasmid Involvement . . 153
IV. Kanamycin . . . . . . . 154
1. Biosynthesis of Subunits 154
2. Subunit Assembly . . 155
3. Plasmid Involvement . . 158
V. Gentamicin and Sisomicin . 159
I. Biosynthesis of Subunits 159
2. Subunit Assembly . . . 160
XII Contents
VI. Spectinomycin (Actinospectacin) 167
1. Biosynthesis of Subunits 167
2. Subunit Assembly . . . 170
VII. Kasugamycin ..... . 171
1. Biosynthesis of Subunits 172
2. Subunit Assembly . 175
3. Plasmid Involvement . . 175
VIII. Validamycin . . . . . . . 176
1. Biosynthesis of Subunits 177
2. Subunit Assembly . . . 177
IX. Miscellaneous Aminoglycosides . 177
1. 1,4-Diaminocyclitol Aminoglycosides 177
2. Monoaminocyclitol Aminoglycosides 179
3. Apramycin . . . . . . . . . . . 179
X. Comprehensive Discussion on the Biosynthesis of Aminoglycosides 180
C. Mutational Biosynthesis (Mutasynthesis) 185
D. Conclusion 191
References . . . . . . . . . . . . . . . 191
CHAPTER 4
Antibacterial Activity of Aminoglycoside Antibiotics. S. MITSUHAsm.
With 9 Figures
A. Introduction ....... . 205
B. Drug Resistance Plasmids . . . 205
I. The Discovery of R Factors 206
II. The Discovery of Nonconjugative Resistance (r) Plasmids 206
C. Resistance Patterns of Bacteria .......... . 207
D. Bacterial Strains Resistant to Aminoglycoside Antibiotics 211
I. Drug Resistance Mediated by R Plasmids . . . . . 212
II. Antibacterial Activity of Aminoglycoside Antibiotics 215
E. Conclusion 219
References . . . . . . . . . . . . . . . . . . . . . . 219
CHAPTER 5
Mechanism of Action of Aminoglycoside Antibiotics. N. TANAKA.
With 21 Figures
A. The Effects on Bacterial Cells and Their Components. . . . 221
I. In vivo Effects on Bacteria in Relation to Mode of Action . 221
II. Interference with Protein Synthesis in vitro. . . . . .. . 222
III. Localization of Drug Sensitivity, Resistance, and Dependence on
the Ribosome . . . . . . . . . . . . . . . . . . . . . . 222
