Advances in Applied Microbiology, Volume 21

ADVANCES IN

Applied MicrobioIogy VOLUME 21

CONTRIBUTORS TO THIS VOLUME

L. T. Fan D. J. D. Hockenhull Philip H. Howard I. C. Kao Keido KO Lloyd E. McDaniel Juan F. Martin Hewitt W. Matthews Tomomasa Misato Prasanta K. Ray Jitendra Saxena

R. H. Shipman E . J. Vandamme

Barbara Fritche Wade Isamu Yamaguchi

ADVANCES IN

Applied Microbiology Edited by D. PERLMAN School of Pharmacy The University of Wisconsin Madison, Wisconsin

VOLUME 21

@

1977

ACADEMIC PRESS, New York San Francisco London A Subsidiary of Harcourt Brace Jovanovich, Publishers

COPYRIGHT 0 1977, BY ACADEMIC PRESS,INC. ALL RIGHTS RESERVED. NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION IN WRITING FROM THE PUBLISHER.

ACADEMIC PRESS, INC.

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United Kingdom Edition published by ACADEMIC PRESS, INC. (LONDON) LTD. 24/28 Oval Road. London N W l

LIBRARY OF CONGRESS CATALOG CARD NUMBER:59-13823 ISBN 0-12-002621-X PRINTED IN THE UNITED STATES OF AMERICA

CONTENTS LIST OF CONTRIBUTORS ..............................................

ix

Production of Polyene Macrolide Antibiotics JUAN

F . MARTIN AND

LLOYD

E . MCDANIEL

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11. Factors Affecting Polyene Macrolide Production ....................... I11. Interaction of Polyene Macrolide Antibiotics with the Producer Cells . . . . . IV . Genetics of Polyene-Producing Streptomyces ..........................

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2 14 37 43 47

Use of Antibiotics in Agriculture

TOMOMASA MISATO. KEIDO KO. AND ISAMU YAMAGUCHI I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. Agricultural Antibiotics and the Pollution Problem . . ...... .... 111. Utilization of Medical Antibiotics as Agricultural Chemicals . . . . . . . . . . . . . . . . . IV . Antibiotics Developed as Agricultural Chemicals ........................... V . Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References ...........................................................

53 54 55

60 82 83

Enzymes Involved in p-Lactam Antibiotic Biosynthesis

E . J . VANDAMME I. I1. 111. IV . V.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structure of B-Lactam Antibiotics ........................................ Biosynthesis Mechanisms of B-Lactam Antibiotics and Their Enzymes . . . . . . . . Terminal-Stage Enzyme Reactions in a-Lactam Antibiotic Biosynthesis . . . . . . . Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89 89 92 97 117 119

Information Control in Fermentation Development

D . J . D . HOCKENHULL I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1 . Research and Development Budget ...................................... V

125 133

vi

CONTENTS

111. Project Initiation Request (Research or Development Program) . . . . . . . . . . . . . .

.......................... V. Periodical Report ................... VI. Laboratory and Plant Protocols . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. The Standard Operating Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII. Direct Experimental Records . . . ...................... M. Miscellaneous In ........... X. Minutes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI. Collection and Flow of Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XII. Making the Best ....................... References . . . . .............................. ..... IV. Formal Program

133 135 138 142 143 146 153 153 134 156 159

Single-Cell Protein Production by Photosynthetic Bacteria

R. H. SHIPMAN,L. T. FAN,AND I. C. KAO I. Introduction . ...................................... 11. Process Consi ............... ................... ...................... 111. Conceptual Design . . . . . . . . . . . . . . . . . . _............. IV. Economic Analysis . . . . . , . , . , . . . . . . . . . . . . . . . References ........................................

161 166 172 176 181

Environmental Transformation of Alkylated and Inorganic Forms of Certain Metals JITENDRA

I. Introduction

SAXENAAND PHILIPH. HOWARD ..................................

185

.................................

186 194 198 205 210 212 215 217 219 220 222

Test Methods for Studying Transformation ..................... Analytical Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Factors Affecting Transformation of Metals . . . . . . . . . . . . . . . . . . . . . . . Biochemical Pathways and Mechanisms for Transformation of Metals . . . . . . . . . General Discussion of Various Test Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Correlation between Laboratory and Field Results and M. Restoration of Metal-Contaminated Areas . . . . . . . . . . . ............ X. Categorization of Elements . . . . . . . . . . . XI. Summary and Conclusions,. , . . . . . . . . . . . . . . . . . . . . . . . References .....................................................

111. IV. V. VI. VII. VIII.

Bacterial Neuraminidase and Altered Immunological Behavior of Treated Mammalian Cells

PRASANTA K. RAY I. Introduction . . . . . . . . . . . . . , . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Receptor-Destroying Enzyme . . . . . . . . . . . . . . . . . . . . . . . . 111. Sialic Acid and Its Relationship to the Antigenicity of the Cell Surface . . . . . . . . 11. Neuraminidase-The

227 228 237

CONTENTS

....... Iv. Increased Immunogenicity of Neuraminidase-Treated Cells . . . . . . V. Regression of Established Solid-Tissue Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . , VI. How Do Neuraminidase-Treated Tumor Cells React in the Host to Establish Specific Antitumor Immunity? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. A Probable Mechanism by Which Neuraminidase-Treated Tumor Cells Give Rise to Specific Antitumor Immunity ..................... VIII. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . .

vii 243 246

249 259 260 261

Pharmacologically Active Compounds from Microbial Origin

HEWITTw. MATTHEWSAND BARBARAFRITCHE WADE I. Introduction . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Types of Pharmacological Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . , . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,

SUBJECTINDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTENTS OF PREVIOUS VOLUMES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

269 269 286

287

289 293

This Page Intentionally Left Blank

LIST

OF CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

L. T. FAN, Department of Chemical Engineering, Kansas State University, Manhattan, Kansas (161)

D. J. D. HOCKENHULL, Glaxo Laboratories Ltd., Ulverston, Cumbria, England (125) PHILIPH. HOWARD,Lije Science Division, Syracuse University Research Corporation, Syracuse, New York (185) I . C. KAo, Biochemical Development Division, Eli Lilly and Company, Indianapolis, Indiana (161)

KEIDO KO, The Institute of Physical and Chemical Research, Wako-shi, Saitama, Japan (53) LLOYD E. MCDANIEL,WaksmunInstitute of Microbiology, Rutgers University, New Brunswick, New Jersey (1) MARTIN,*Departmnt of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, Massachusetts (1)

JUAN F.

HEWITTW. MATTHEWS, Southern School of Pharmucy, Mercer University, Atlanta, Georgia (269) TOMOMASAMISATO,The Institute of Physical and Chemical Research, Wako-shi, Saitamu, Japan (53) PRASANTAK. RAY, Chittaranjan National Cancer Research Centre, Calcutta, India (227) JITENDRA SAXENA, Li$e

Science Division, Syracuse University Research Corporation, Syracuse, New Ym-k (185)

R. H. SHIPMAN, Department of Chemical Engineering, Kansas State University, Manhattan, Kunsas (161) *Present address: Departamento de Microbiologia, Facultad de Ciencias, Universidad de Salamanca, Salamanca, Spain.

ix

X

LIST OF CONTRIBUTORS

E. J. VANDAMME,Laboratory of General and Industrial Microbiology, University of Gent, Gent, Belgium (89) BARBARAFRITCHEWADE, Southern School of Pharmacy, Mercer University, Atlanta, Georgia (269) ISAMUYAMAGUCHI, The lnstitute of Physical and Chemical Research, Wakoshi, Saitama, Japan (53)

Production of Polyene Macrolide Antibiotics JUAN

F. MARTIN^

Department of Nutrition and Food Science, Massachusetts lnstitute of Technology, Cambridge, Massachusetts AND

LLOYDE. MCDANIEL Waksman Institute of Microbiology, Rutgers University, New Brunswick, New Jersey I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. History of the Discovery of New Polyene Macrolide Antibiotics .......................... . . . . . . . . . . . . . . . B. Chemical Characteristics of Polyene Macrolide Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Microbial Species That Produce Polyene Macrolide

..................... A. B. C.

D. E. F. G. H. I. J.

K.

.......

ene Macrolide Production . . . . . . . . . . . . Nutritional Studies ................................. Carbohydrates as Carbon Sources . . . . . . . ........ Relation to the Utilization of Short-Chain Fatty Acids and Alcohols . . . . . . . . . . . . . . . Role of Oxaloacetate . . . . Role of Citrate . . . . . . . . . ...... Interrelation with Fatty Acid Biosynthesis . . . . . . . . . . . . . Nitrogen Sources ..................... ...... Regulation by Arcmatic Amino Acids . . . . . . . . . . . . . . . . . . Effect of Inorganic Orthophosphate . . . . . . . . . . . . . . . . . . . Regulation of the Biosynthesis of Polyene Macrolide Antibiotics by Adenine Nucleotides and/or the Energy Charge of the Cell .................................. Effect of Metal Ions. . . . . .

M. Effect of Redox Potential . . . . . . . . . . . 111. Interaction of Polyene Macrolide Antibioti Producer Cells . .

2 2 3 12 14 14 15 17 20 21 22 24 25 27

31 33 34 36 37 37

Production ........................... C. Polyene Macrolide Production in Mixed Culture with

......................................... D. Susceptibility of the Producer Strains to Polyene Macrolide Antibiotics ............................... E. Feedback Regulatory Effect of Polyene Macrolide Antibiotics on Their Own Production. . . . ...

39 40 41 42

'Present address: Departamento de Microbiologia, Facultad de Ciencias, Universidad de Salamanca, Salamanca, Spain. 1

2

JUAN F. MARTIN AND LLOYD E . MCDANIEL

IV. Genetics of Polyene-Producing Streptomyces ............... A. Natural Variants of Soil-Isolated Strains and Mutational Strain Improvement ................................ B. Effect of Actinophages on Antibiotic Production-Lysogenic Conversion of Antibiotic-Producing Strains ......................... References ............................................

43 43

45 47

1. Introduction

A. HISTORYOF THE DISCOVERY OF NEW POLYENE MACROLIDEANTIBIOTICS Since the early 195Os, when the first polyene macrolide antibiotics were reported, more than 90 different members of this group have been described, and more are being discovered each year. Sixteen polyene macrolides were known in 1957 (Dutcher, 1957), 41 in 1960 pining, 1960), 57 in 1963(Oroshnik and Mebane, 1963), and 84 in 1973 (Hamilton-Miller, 1973). Several more, which have been reported recently, are included in Table I. However, one must be cautious in considering many of these antibiotics to be new, since the question of the identity of many remains open. Most polyene macrolides have not been obtained in pure form, and the chemical compositions of most of them are unknown. Thus, tennecitin and pimaricin have been found to be the same; also lagosin and fungichromin. Polifungin A is identical with nystatin (Porowskaet al., 1972; Roszkowskiet al., 1972), but polhngin B is different from the latter. The pentaenes mycoticins A and B are identical, respectively, with the minor and major components of flavofungin and flavomycoin (Bognar et al., 1970; Uri and Bekesi, 1958). It appears also that the aromatic heptaene macrolides candicidin, trichomycin, levorin, and hamycin are in fact mixtures in different proportions of the same components rather than separate entities. It has been suggested that hamycin and trichomycin are identical (Divekar et al., 1966)and that candicidin is identical with trichomycin (Khokhlovaet al., 1963). Pyrolysis gas chromatography of these heptaene macrolides suggests that they are mixtures, with a single identical main component and varying proportions of similar minor components (Burrows and Calam, 1970; Calam, 1974). Countercurrent distribution studies indicated that of the four components of the levorin complex (&, Al, A,, A3), A,, the main component of the complex, is not distinguishable from the main component of candicidin (Bosshardt and Bickel, 1968). Khokhlova et al. (1963) indicated that strains of Streptomyces griseecs which produce candicidin, Streptomyces canescus (the producer of ascosin), and Streptomyces levoris (the producer of levorin) are the same species, but

PRODUCTION OF POLYENE MACROLIDE ANTIBIOTICS

3

that Streptomyces hachijoensis (the producer of trichomycin) is different. A new polyene antibiotic isolated from Streptomyces helvoloviolaceous is identical with component A3 of the levorin complex (Konev et al., 1973).

B. CHEMICAL CHARACTERISTICS OF POLYENE MACROLIDEANTIBIOTICS The polyene macrolides form a subdivision of the macrolide antibiotics containing hydroxylated macrocyclic lactone rings and usually one or more sugars. Biogenetically the macrolides are a homogeneous group, being synthesized from acetate and propionate via the polyketide pathway (Bu’Lock, 1967). The macrolide antibiotics are divided into two subgroups: (a) polyene antifingal antibiotics and (b) nonpolyene antibacterial antibiotics. The polyene subgroup has a system of conjugated double bonds, or chromophore, in the macrolactone ring. This results in an amphipathic molecule containing both a rigid planar lipophilic portion and a flexible hydrophilic polyhydroxylated region. The chromophore accounts for some of the characteristicphysical and chemical properties of the polyenes (strong light absorption, photolability, and poor solubility in water) and appears to be responsible for the differences in the biological modes of action of the polyene and the nonpolyene macrolide subgroups. The chromophorc gives a typical multipeak ultraviolet-visible light absorption spectrum which permits a rapid characterization and division of the polyene macrolides into dienes, trienes, tetraenes, pentaenes, hexaenes, and heptaenes according to the number of conjugated double bonds in the chromophore. A classification of the existing polyenes is given in Table I. The polyene macrolides have lactone rings of 26-38 atoms, which are much larger than those of the nonpolyene macrolides (e.g., a 14-membered lactone in erythromycin). The aminosugars and aromatic moieties found in polyene macrolide antibiotics attached to the macrolide rings are shown in Fig. 1. Recently, a new class of nonpolyene antifungal macrolides, the axenomycins, with large 34-member lactone rings has been reported. This group appears to be closely related in structure and biological activity to the polyene macrolides in spite of their nonpolyene character (Bianchi et al., 1974). Although purification of polyene macrolide antibiotics is difficult because of their low solubility and instability to heat and light, considerable progress has been achieved in recent years in the determination of the complex chemical structure of these compounds by utilizing sensitive analytical methods, such as electron impact and field desorption mass spectrometry (Rinehart et al., 1974), proton magnetic resonance, and X-ray structure analysis of single crystals for absolute configuration determination

P

TABLE I POLYENE MACROLIDE ANTIBIOTICS (CODENUMBER 22) Berdy's classification" Code number Name (alternative names) ~~~~~~~~~~~

Amino sugar moiety

Producer strain ~

~

Nitrogen

Ionic character

~~~

221 TFUENES (A maxima 262, 272, 283 nm) 2211 Trienin type Streptomyces sp. Mycotrienin Streptomyces sp. Trienine Antibiotic MM-8 Sheptomyces sp. Triene Chainia minutisclerotina 2212 Other trienes Resistaphyllin S. antibioticus 222 TETRAENES (A maxima 291, 304, 308 f 2 nm) 2221 Pimuricin type S . tumemomucerans var. Aeromycin B (P-42-E) griseoarenicolor S . lucensis Etruscomycin (lucensomycin) (1163 FI) S . natalensis, Pimaricin (tennecetin) S . chattanoogensis, S . gilveosporus S . noursei var. Tetramycin jenensis Streptomyces sp. Tetrin A, B Antibiotic PA-I66 Sheptomyces sp.

-

NDb ND None ND

Yes Yes Yes ND

ND

Yes

-

Mycosaminec

Yes

-

Mycosamine

Yes

Amphoteric

M ycosamine

Yes

Amphoteric

Mycosamine

Yes

-

Mycosamine Mycosamine

Yes Yes

Amphoteric Amphoteric

Neutral

-

Aromatic moiety

2222 Rimocidin type Akitamycin S. akitaensis, (toyamycin) S. toyamaensis S. albus sterilis Albotetraen Rimocidin S. rimosus (PA-86) Antibiotic RP-9971 S. gascariensis 2223 Nystatin type Amphotericin A S. nodosus Nystatin A,, A*, A3 S. noursei, S. albulus (fungicidin) (polifungin) S. plumbeus Phmbomycin A Plumbomycin B S . plumbeus 2224 Other less-known tetraenes Antimycoin A S. aureus Chromin S. chromogenes Endomycin A S. endus (helixin A) Flavoviridomycin S. flavoviridus var. fungicidicus, S. hygroscopicus var. enhygrus Ornamycin (17731) S. erumpens, S. ornatus Protocidin Streptomyces sp. NO. 964-A Sistomycosin s. viridosporus Tetraenin A, B Chainia cinnamonea Tetramedyn S. mediocidicus Tetramycoin A, B Chainia grisea, Chainia grisea var. fusca

ND

Yes

Amphoteric

ND M ycosamine

Yes Yes

Basic

ND

Yes

Amphoteric

Mycosamine Mycosamine

Yes Yes

Amphoteric Amphoteric

ND ND

Yes Yes

ND ND ND

-

Yes Yes

Acid Amphoteric

ND

Yes

ND

Yes

Amphoteric

ND ND ND ND

Yes

-

Yes

-

-

(Continued)

VI

TABLE I (Continued) Berdy's classification" Code number Name (alternative names) Unamycin A Antibiotic A-5283 Antibiotic AC2-435 Antibiotic J4-B

Producer strain

S. fungicidicus Streptomyces sp. A5283 Streptomyces sp. ACz-435 Streptomyces sp. (S.fungicidicus) Streptomyces sp. Streptomyces sp. 0777

Antibiotic RP-7071 Antibiotic LIA 0777 223 PENTAENES 2231 Methylpentaenes (aldopentaenes) (A maxima 327, 340, 357 2 2nm) Aurenin S. aureorectus Cabicidin s. gougeroti Chainin Chainia sp. 3047 S. fdipensis Filipin complex (durhamycin) S . cinnamoneus var. Fungichromin cinnamoneus, (moldcidin B) (pentamycin) S. roseoluteus, (Gkxo-A246) S. cellulosae, (Lagosin) S. pentaticus Fungichromatin S. cellulosae Pentaneicin Streptooerticillium sp. S. sanguineus Pentaene Neopentaene Streptomyces sp. S. rubrochlm'nus Rubrochlorin Xantholicin B S. rantholiticus Antibiotic HA-106 Streptooerticillium cinnamoneum var. sparsum

cn

Amino sugar moiety

Nitrogen

Ionic character

Mycosamine ND ND ND

Yes Yes No No

Acid Amphoteric -

ND Mycosamine

Yes Yes

Basic Amphoteric

None None None None

No No No No

Neutral Neutral Neutrd

None

No

Neutrd

None None None None None None None

No No No No No No No

-

Aromatic moiety

-

Acidic

-

-

-

?

r

s0 P

Antibiotic HA-135

Streptoverticillium sporiferum Antibiotic HA-145 Streptooerticillium cinnamneum var. albospwum Antibiotic HA-176 Streptoverticillium cinnamoneum var. lanosum 2232 “Normal” pentaenes (amphoteric pentuenes with amino sugar)(h maxima 317, 331, 350 ? 2 nm) Aliomycin S. acidomyceticus Distamycin C S . distallicus Eurocidin A S . eurocidicus, S . albireticuli Eurocidin B S. albireticuli Fumanomycin S . laoendobrunneus Moldcidin A S . griseofuscus, Streptomyces sp. S. sp. J-4(S. fungicidicus) Onomycin I Pentafungin S. antimycoticus Pentaene G-8 S . anandensis Quinquamycin S . laoendulae E-20-27 Streptomyces sp. Antibiotic A-228 Antibiotic PA-153 Streptomyces sp. Sh-eptomyces sp. 17-41 Antibiotic 17-41 B Antibiotic 0371 Streptovetticillium jenensis krissii 2233 “Normal” pentaenes. (Capacidin type) Capacidin S. noursei (variant) 2234 Gangtokumycin type Gangtokumycin S . gangtokensis ( S . hygroscopicus)

None

No

None

No

None

No

ND ND M ycosamine

-

-

Yes

Amphoteric

Mycosamine ND Mycosamine

Yes Yes Yes

Amphoteric

ND ND ND ND ND ND ND

Yes Yes

Acidic Amphoteric

-

-

Yes Yes

Neutral Amphoteric

Yes

-

-

Yes

-

Yes

-

Yes

sl

Acidic

-

Basic

(Continued)

4

TABLE I (Continued) 00

Berdy's classification" Code number Name (alternative names)

Producer strain

Genimycin Actinosporangium sp. 2235 Carbonyl pentaenes ( h maxima 364 nm; broad peak) Flavohngin S. ruber, (mycoticin A) S. jlavofungini Flavomycoin S. roseoflavus var. jenensis Mycoticin B S. jlaoofungini Surgomycin S . surgutus 224 HEXAENES (A maxima 340, 358, 380 ? 2 nm) 2241 Probably macrocyclic heraenes S . oiridojlavus var. 18A2 Candihexin A, B S. viridoflavus var. 18A2 Candihexin E, F Cryptocidin Streptomyces sp. 963, S. bulgaricum Hexin Streptomyces sp. S. endus, Endomycin B (helixin B) S. hygroscopicus var. enhygrus Flavacid s. jlavus Mediocidin S . mediocidicus Tetrahexin Streptomyces sp. (tetraesin) ATCC 14972 2242 Fradicin type (unknown structures) Fradicin S . fiadiae Mycelin S . roseojlavus, S . diastatochromogenes, S. fiadiae

Amino sugar moiety

Nitrogen

Ionic character

-

Yes

-

None

No

Neutral

None

No

-

None ND

No

Neutral

Aromatic moiety

* W

Mycosamine None ND

Yes Yes Yes

ND ND

-

None ND ND

Yes Yes Yes

Acid Amphoteric Amphoteric

ND ND

Yes No

Basic

Acid

P

6

B

-

-

Mycelin IMO Antibiotic A-1404

S. diastatochromogenes S. fi-adiae A-1404, S. diastatochromogenes 207

2243 Carbonyl hexaenes (A maxima 385 nm; broad peak) S. uiridogsiseus Dermostatin (viridofulvin) 225 HEF'TAENES 2251 Aromatic heptaenes 22511 Containing p-aminoacetophenone S . paucisporogenes Antifungin 4915 Ascosin S. canescus Ayfactin, S. aureofaciens, S. uiridofaciens (AYF), (AE-56), (Aureofacin) S. cinnamoneus Aureofungin var. terricola Azacolutin S. cinnamoneus (F-17-C) var. azacoluta S. griseus Candicidin (G-252) (PA-150) S. griseus H-5592 Eurotin A S. jujuy ATCC 13670 Gerobriecin Hamycin S. primprina S. longisporolavendulae Heptafungin A S . leuoris Levorin Ao, A,, Az, A,, B (26/1)

ND ND

Yes

None

No

Neutral

ND Mycosamine Mycosamine

Yes Yes Yes

ND Amphoteric Acid

ND p-Aminoacetophenone p-Aminoacetophenone

Mycosamine

Yes

Amphoteric

p-Aminoacetophenone

ND

Yes

Amphoteric

p-Aminoacetophenone

Mycosamine

Yes

Amphoteric

p-Aminoacetophenone

ND ND Mycosamine Mycosamine Mycosamine

Yes Yes Yes Yes Yes

Basic ND Amphoteric Amphoteric Amphoteric

p -Aminoacetophenone ND p-Aminoacetophenone p-Aminoacetophenone p-Aminoacetophenone (Continued)

TABLE I (Continued) Berdy's classification" Code number Name (alternative names) Trichomycin A, B

Producer strain

S. hachijoensis, S . abikoends S . surinam Actinoplanes sp.

DJ-400Bz Sch 16656 22512 Containing N-mthylp-aminoacetop henone Candimycin S . echimensis DJ-400 B, Perim ycin (NC-968) (Fungimycin) (Aminomycin) 2252 Nonaromatic heptaenes Amphotericin B Candidin (Candidoin) (Candidinin) Mycoheptin (2814 H)

Amino sugar moiety

Nitrogen

Ionic character

Aromatic moiety

Mycosamine

Yes

Amphoteric

p- Aminoacetophenone

Mycosamine ND

Yes Yes

Amphoteric

p-Aminoacetophenone p-Aminoacetophenone

ND

.h

5 IJ

e %CI

ND

Yes

ND

N-Methyl?aminoacetophenone

S surinam

Mycosamine

Yes

Amphoteric

N-Methyl?aminoacetophenone

3

S. coelicolor var. aminophilus

Perosamined

Yes

Basic

N-Methyl?-

r

.

aminoacetophenone

r

ei z

S . nodosus S . oiridofious

Mycosamine Mycosamine

Yes Yes

Amphoteric Amphoteric

None None

Streptoowticillium mycoheptinicum, S . netropsis

Mycosamine

Yes

Amphoteric

None

S. chartreusis var. tbilisus Antibiotic X-63 Streptomyces sp. Antibiotic A-3 Streptomyces sp. 2253 Noncharacterized heptaenes Grubilin Streptomyces sp. BA-27 Heptamycin Streptomyces sp. Hepcin Actinosporangium griseoroseum Heptaene 757 Streptomyces sp. 757 Monicamycin Streptoverticillum annamoneum var. monicae Neoheptaene Streptomyces sp. S . noursei Nursimycin Takamycin S . takaensis, S . reticuli C-11 Antibiotic 26/1 S. globisporus Antibiotic 2814-H Streptomyces sp. IA-2814 Antibiotic 1645-P, Streptomyces sp. 1645-IAUR LIA 0331 S. chromogenes LIA 0179 Streptomyces sp. Tbilimycin

Mycosamine

Yes

ND

None

ND ND

Yes Yes

ND ND

None None

ND ND ND

ND ND ND

ND Acid ND

ND ND ND

ND ND

ND ND

Acid Acid

ND ND

ND ND ND

ND ND ND

ND ND ND

ND ND ND

ND ND ND

ND Yes Yes

Amphoteric Amphoteric ND

ND ND ND

ND ND

ND ND

ND ND

ND ND

“Berdy (1972). bNo data available. c3-Amino-3, 6-dideoxy-~-mannose. d4-Amino-4,6dideoxy-~-mannose. c c

12

JUAN F. MARTIN A N D LLOYD E . MCDANIEL

isoxazolyl penicillins > gentamicin > aminosidin > spiramycin 2 ampicillin. The action of the tetracyclines varied with the specific antibiotic used and with the percentage of the 4-epiderivatives in the tetracycline used. That is, mepicycline inhibited the spasm-producing effect of barium chloride, whereas tetracycline and rolitetracycline increased this effect. The greater the 4-epiderivative concentration, the greater the stimulating action of barium chloride. There were no significant differences in the activities of tetracycline, oxytetracycline, and chlortetracycline. Triggle et aZ. (1975) investigated the effects of the ionophone A23187 on intestinal smooth muscle contraction. This ionophore produced a contraction of guinea pig ileal longitudinal muscle that was dose dependent. The initial contraction was very rapid, followed by a slow return to a normal relaxed state. Moreover, the tissue remained in an enhanced state even after the drug was washed out. Since the presence of calcium was necessary for the activity of ~ ~ 3 1 8it7 is , possible that this ionophore induces a contraction by transporting calcium from the outside to the inside of the smooth muscle or by affecting the release of calcium from sarcoplasmic reticulum. G. EFFECTSON FERTILITY The inhibitory effect of twenty-one antibiotics on the motility of spermatozoa of various animals and man was studied by Fuska et al. (1973). Only frequentin (isolated from Penicillium fj-equentans) and cyclopaldic acid to-

280

HEWITT W. MATTHEWS AND BARBARA FRITCHE WADE

tally stopped the movement of spermatozoa within 5 minutes. Frequentin, in concentrations of 20-80 pg/ml, had the greatest effect on bull's semen but the least effect on semen from rabbits and bucks. An evaluation of the biochemical effect of frequentin on sperm indicated a decreased vitality of the sperm by this substance. Cyclopaldic acid inhibited the movement of sperm only at concentrations from 400 to 500 pglml. The results of the various antibiotics tested are shown in Table IV. Timmermans (1974) reported on the effects of ten antibiotics on the spermatogenesis in animals. From the results obtained, it was possible to classify these substances into three groups based on their effects on sperTABLE IV

EFFECTOF ANTIBIOTICSON

THE

MOTILITYOF SPERMATOZOA" Influence on motility

Antibioticb Bacitracin Chloramphenicol Cycloheximide Erythromycin lactobionate Helvolic acid Kojic acid Neomycin sulfate Penicillin G (potassium salt) Streptomycin sulfate Tetracycline HCI Viomycin sulfate Amphotericin B Chlorotetracycline HCI Citrinin Cyanein Griseofulvin Palitantin Penicillic acid Trichothecin Cyclopaldic acid Frequentin

Mechanism of actionC

P, P

cw

NA P

Toxicity

of

(LDS0,pg/ml)

spermatozoae

342 1320 300 1800

400 250

NA, P

cw NA, P, CW P

P

cw P

cw NA, P NA

4450 None 200 330 240 26 192 200 200 280 250

cw

N N N N N N N N N N N

I I

I

I I I I

I

s S

nFrom Fuska et al. (1973). q h e concenbation of antibiotics in all experiments was 500 pg/ml of semen. 'P = synthesis of proteins; CW = cell wall synthesis; NA = synthesis of nucleic acids; N = motility of spermatozoa not inhibited; I = motility of spermatozoa inhibited within 3 hours by the added substances; S = substances totally stopped the movement of spermatozoa within 5 minutes.

PHARMACOLOGlCAL AGENTS FROM MICROORGANISMS

28 1

The first group, including gentamicin sulfate, N(5-nitrohrfuryllidene)-l-aminohydantoin, and oxytetracycline, stopped spennatogonia division and inhibited spermatocytes I meiosis. Oxytetracycline had the smallest effect in this group. The second group, containing colymyspiramycin, sodium-7-(thiophene-2-acetamido)-cephalo-sporanate, cin methane sulfonate, and framycetin, showed an alteration of mitosis in spermatogonia. In the third group, potassium penicillin G , chloromycetin succinate, and trimethoprim showed partial or complete inhibition of the spermatogonial division and aggravated meiosis in most spermatocytes. Timmermans (1974)observed that the action of the antibiotics seemed to be specifically on germ cells rather than on interstitial tissue. matogenesis.

RELEASE H. EFFECTSON HORMONE Hertelendy et al. (1971)found that valinomycin inhibited the in uitro responses of prostaglandin El dibutyryl cyclic AMP, theophylline, and K+ on the stimulation of growth hormone release. Based on experimental results, it was postulated that the site of action was not at the adenyl cyclase level, but rather distal to this site. It is possible that this antibiotic interferes with the energy metabolism of the pituitary cells. Russell et a2. (1974)observed the effect in uitro of the ionophore A23187 on release of vasopressin from the neurohypophysis. The neurohypophyses of rats were incubated in a calcium-&eemedium with A23187.When calcium was added to the medium, there was a significant increase in vasopressor release. When labeled 45Ca was used, addition of the ionophore to the medium caused an increased efflux of the ion. From these experiments, it seemed that A23187 increased the transport of calcium &om outside the cell to the inside, a step that is necessary for vasopressin release. Grenier et al. (1974)studied the effect of A23187 on thyroid secretion. They found that those thyroid functions needing extracellular calcium for their actions were positively affected by A23187. These functions were the activation of glucose carbon-1 oxidation and the binding of iodide to proteins.

I. DIABETOGENIC EFFECTS Schein and Bates (1968)compared plasma glucose levels in mice treated with streptozotocin with those pretreated with nicotinamide. Streptozotocin, an antitumor agent produced by Streptomyces achromogenes, had been observed to destroy the pancreatic beta cells of test animals. In this experiment both control and nicotinamide-protected mice showed an initial hyperglycemic phase after administration of 175 mg of streptozotocin per kilogram. This early elevation of blood sugar was not dependent on the

282

HEWITT W. MATTHEWS AND BARBARA FRITCHE WADE

presence of an adrenal gland but was drug related. After 7 hours, the animals treated with only streptozotocin showed a hypoglycemic phase, associated with increased plasma levels of immunoreactive insulin. After 24 hours, these mice were permanently diabetic. The group receiving 500 mg of nicotinamide per kilogram remained protected and showed no evidence of diabetes. Beloff-Chain and Rookledge (1968) studied the metabolism of glucose in diaphragm muscle obtained from normal rats, streptozotocin-treated diabetic rats, and rats treated with anti-insulin serum. It was found that the formation of glycogen and oligosaccharides from labeled [ 14C]glucosewas decreased in both the diabetic and anti-insulin-treated rats. Neither state influenced the oxidation of glucose or the formation of lactate and hexose phosphate esters from glucose. In the presence of insulin, the diabetic muscle resumed its ability to incorporate glucose into glycogen. Although its ability to form oligosaccharides increased somewhat, these levels never returned to normal values. Kushner et al. (1969) found that rabbits and guinea pigs receiving a maximum dose of 130 mg of streptozotocin per kilogram were resistant to the diabetogenic effects of streptozotocin, whereas rats became diabetic. This effect in rabbits and guinea pigs was apparently not due to rapid metabolism or lack of absorption of streptozotocin, because the blood levels of the drug remained high. Thus, it is possible that the drug may exert its effect on a specific metabolic pathway that is species dependent. Since nicotinamide administration prevents the formation of diabetes in rats, it is possible that streptozotocin blocks the synthesis of N A D from nicotinamide in rats but has little or no effect on N A D synthesis from nicotinic acid, the pathway that may be preferentially employed by rabbits and guinea pigs. Veleminsky et al. (1970) compared the early metabolic events resulting from administration of the two diabetogenic agents alloxan and streptozotocin. Either 65 mg of streptozotocin or 60 mg of alloxan per kilogram produced similar degrees of pancreatic insulin depletion 48 hours after administration, resulting in metabolic changes indicative of acute diabetes. These metabolic changes were ultimately the result of beta-cell destruction. In a similar study, Forster and Rudas (1969) showed that rats made diabetic with streptozotocin developed a transient ketosis which disappeared after 7 days. Woods et al. (1970) used strepotozotocin to produce a diabetic state for their studies on conditioned insulin secretion in the albino rat. Pitkin and Reynolds (1970)observed that doeses of 60 mg of streptozotocin per kilogram could produce diabetes in rhesus monkeys. However, the diabetogenic dose of streptozotocin in these animals was very close to the toxic dose. Histological studies revealed decreased numbers of pancreatic islets, and during the first few days after streptozotocin administration the islets contained

PHARMACOLOGICAL AGENTS FROM MICROORGANISMS

283

virtually no beta cells. Other accounts of the diabetogenic activity of streptozotocin include those of Golob et al. (1970a,b), Wyse and Dulin (1971), Beloff-Chain et al. (1971), and Beloff-Chain and Rookledge (1972).

J. HYPOCHOLESTEROLEMIC EFFECTS Van den Bosch and Claes (1967) attempted to correlate the bile saltprecipitating capacity of derivatives of basic antibiotics in vitro and their plasma cholesterol-loweringeffectsin oiuo. Derivatives of streptomycin and neomycin were synthesized to observe whether increasing the number of basic groups on the molecule would form a compound more active than the parent compound. Their effects on bile salt solutions, on resorption of lithocholic acid, and on plasma cholesterol levels in chickens were investigated. The effects of only one derivative (N-methylatedneomycin) on plasma levels and on fecal bile salt excretion in humans was also observed. The following derivatives of neomycin were prepared: N-methylated neomycin, N-methylated neomycin methochloride, and N-hexaacetylneomycin. The two derivatives of streptomycin were synthesized by condensation of streptomycin trihydrochoride with di- and triaminoguanidine hydrochloride to obtain distreptomycylidene-diaminoguanidine heptahydrochloride and tristreptomycylidene-diaminoguanidine decahydrochloride. When dilutions of these substances were added to solutions of sodium glycodeoxycholate, precipitates of the bile salt were observed for all substances except streptomycin and N-hexaacetylneomycin. These results were consistent with the basicity of the molecules, since streptomycin contains only three basic groups and N-hexaacetylneomycin is not basic. In the streptomycin series there was a sharp increase in the precipitating capacity with an increased number of basic groups per molecule. In tests on newly hatched chicks fed a semisynthetic casein sucrose diet supplemented with 0.25% cholesterol, again those substances which initially precipitated bile salts also decreased plasma cholesterol levels. A diet with 2% tristreptomycincylidenediaminoguanidine decahydrochloride lowered plasma levels nearly to normal values. Human volunteers given doses of either 3 or 6 gm/day of N-methylated neomycin showed a sharp decrease in plasma cholesterol levels after 20 days. It was also observed that feces of subjects given N-methylated neomycin contained increased amounts of bile salts and sterols. No objective or subjective side effects of N-methylated neomycin were observed. In a similar study, Eyssen et aZ. (1971) prepared N-methylated, N-acetylated, and dimethylaminopropyl derivatives of neomycin to observe the effect of these polybasic antibiotics on absorption and excretion of cholesterol and bile salts. These derivatives were chosen for this experiment in an

284

HEWITT W . MATTHEWS A N D BARBARA FRITCHE WADE

TABLE V EFFECTOF NEOMYCIN, STREPTOMYCIN, AND THEIR DERIVATIVES ON SERUM AND LIVERCHOLESTEROL LEVELSOF NEWBORN CHICKS

Treatment' N-Methylated neomycin N-Acetylated neomycin DimethylaminoProPYl neomycin Streptomycin Distreptomycinb TristreptomycinC

Serum cholesterol

Liver cholesterol

-22%

-44%

+4%

-59%

--10% -78%

+8%

-5%

-20% -45%

-26%

-75%

aTwenty chicks per group after 2 weeks. Diets contained 0.2%of the test substance. *Distreptomycylidene-diaminoguanidineheptahydrochloride. Tristreptomycylidene-triaminoguanidine decahydrochloride.

attempt to show that their hypocholesterolemic effect was a result of their basicity, not of their antimicrobial properties. Thus, the N-methylated compound contained six basic groups, the N-acetyl substance was neutral, and the dimethylaminopropyl derivative possessed more basicity than the N-methylated compound. Similarly, two basic derivatives of streptomycin were prepared: (a) distreptomycin containing seven basic groups, and (b) tristreptomycin containing ten basic groups. Streptomycin, with only three basic groups, was not expected to have any effect on cholesterol concentrations. The data are summarized in Table V. It can be seen that, as expected, streptomycin and N-acetylated neomycin had very little effect on serum and liver cholesterol levels, whereas the most basic substances, tristreptomycinand the dimethylaminopropylneomycin had the greatest effect. In addition, fecal concentrations of bile salts increased with those substances that showed a hypocholesterolemic effect. Experiments with neomycin and germfree chicks also showed an increased fecal excretion of bile salts and a lowering of the serum and liver cholesterol concentrations. This would indicate that the antibiotic activity, yielding alterations of intestinal microflora, was not responsible for the observed results. These polybasic substances must have a direct effect on cholesterol and bile salts.

285

PHARMACOLOGICAL AGENTS FROM MICROORGANISMS

Samuel et a2. (1973)observed the effect of neomycin on serum cholesterol levels and the 7-a-dehydroxylationof bile acids by fecal bacteria in humans. Oral administration of 2 gm of neomycin lowered serum cholesterol levels from 316 mg/100 ml of plasma to 237 mg/100 ml of plasma. In addition, 7-a-dehydroxylation was decreased from 89% to 9%. Similar results were obtained with kanamycin, chloramphenicol, and chlortetracycline. In several patients where these various drugs did not lower serum cholesterol, there was also observed to be no bile acid degradation. Sasaki et al. (1973), in screening for hypolipidemic agents, isolated ascofuranone and ascofuranol from an ascochlorin-producing fungus, Ascochyta viciae. Ascofuranone was found to lower lipid levels in mice and rats. In a subsequent paper, Sawada et al. (1973)reported on the pharmacological properties of this new hypolipidemic agent, ascofuranone. Its LD5,, was found to be high for both mice and rats; diarrhea was the only side effect observed with large doses. After a single oral dose of ascofuranone, serum cholesterol levels were observed to be as low as or lower than those of the positive control agent clofibrate. Doses for each drug were approximately 108 mgkg. Serum triglyceride, phospholipid, and free fatty acid levels were also determined for both ascofuranone and clofibrate. It was observed that ascofuranone lowered serum triglyceride and free fatty acid levels more than the control clofibrate. Serum phospholipid levels after ascofuranone administration were only 2%higher than the clofibrate control. To test the effects of ascofuranone and clofibrate on long-term treatment, rats were given doses of 20 and 30 mg/kg, respectively, for 10 days. Clofibrate lowered serum lipid levels more than did ascofuranone. The results of this treatment are shown in Table VI. When the organ weights of these rats were measured, it was found that hepatomegaly, accompanied by atrophy of the spleen and heart, occurred with clofibrate. Although ascofuranone treatment slightly reduced the 1iver:body weight ratio, liver function was normal. When heart cholesterol content was deterTABLE VI BY ASCOFURANONE EFFECTOF CONSECUTIVE 10-DAYTREATMENT ON SERUM LIPIDLEVELS

Agents

Serum cholesterol (% change)

Serum triglyceride (% change)

phospholipid (% change)

Serum free fatty acid (% change)

Ascofuranone Clofibrate

-16.5 -23.9

-44.3 -48.4

-33.8 -40.8

-20.2 -24.3

Serum

286

HEWITT W. MATTHEWS A N D BARBARA FRlTCHE WADE

mined, it was found that ascofuranone lowered total heart cholesterol about 14% whereas clofibrate had no effect. Micklewright and Trigger (1974) observed that cholesterol absorption was reduced in small laboratory animals fed the antihngal agent candicidin. With a candicidin dose of 100 mg/kg for rats, cholesterol absorption was reduced to an average value of 23.7%. Studies with mice indicated that absorption of cholesterol was reduced to 8.8%. Similar results were obtained with hamsters, guinea pigs, and rabbits. Oral and intraperitoneal administration of the antibiotic hamycin caused a decrease in plasma cholesterol levels to about 40% of the initial levels after 120 hours (Dave and Parekh 1975). Hamycin was not thought to prevent absorption of cholesterol levels in rats. Doses of 1 m&g per day resulted in a maximum decrease in serum cholesterol of 25% after 4 days. Thereafter, serum cholesterol levels returned to normal, and no dgerence was observed with continued treatment. On autopsy no gross morphological or histological changes in the organs were observed, indicating that amphotericin B’s mode of action is direct rather than through organ damage.

K. MISCELLANEOUSACTIVITIES Phansalkar and Balwani (1970) observed the effects of various antibiotics on hexobarbitone sleeping time in rats. Streptomycin, erthromycin, and spiramycin were observed to significantly shorten the mean sleeping time of these animals. Ogata et al. (1974) reported of a cholinesterase inhibitor produced by Asper-gillus terreus. This inhibitor, labeled 1-6123, was tested on esterases from Pseudomnas aer-uginosa, Electrophorus electricus, horse serum, and pig liver, under conditions where substrate inhibition does not occur. 1-6123 strongly inhibited the nonspecific pig-liver esterase and only weakly inhibited the others. 111. Summary

Since microorganisms provide such a wide variety of metabolic metabolites (i.e., amino sugars, macrolides, pyridines, etc.), it would seem reasonable to assume that microbial metabolites would be excellent sources of pharmacological compounds. Some of the aforementioned compounds reviewed were found to have pharmacological properties secondary to their antibiotic properties. Perhaps if greater emphasis were placed on seeking microbial products with pharmacological activities rather than antibiotic activities, a greater variety of compounds would be available for clinical use.

PHARMACOLOGICAL AGENTS FROM MICROORGANISMS

287

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288

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W.

MATTHEWS AND BARBARA FRITCHE WADE

McQuillen, M. P., and Engback, I. (1973). Trans. Am. Neurol. Assoc. 98, 86-89. Micklewright, P. F., and Trigger, D. J. (1974). J . Pharm. Pharmacol. 26, 10&109. Nakamua, S., Marumoto, Y., Miyata, H., Tsukada, I., Tanaka, N., Ishizuka, M., and Umezama, M. (1969). Chem. P h a m . Bull. 17, 2044-2048. Nakamura, S., Hamada, M., Ishizuka, M., and Umezawa, H. (1970a). Chem. Phunn. Bull. 18, 2112-2118. Nakamura, S., Hamada, M., and Umezawa, H. (1970b). Chem. Fhann. Bull. 18, 2577-2581. Nakamura, S., Fukuda, H., Yamamoto, T., Ogura, M., Hamada, M., Matsuzaki, M., and Umezawa, H. (1972). Chem. P h a m . Bull. 20, 385-390. Nakamura, T., Yasuda, H., Obayashi, A,, and Tanabe, 0. (1975). J . Antibiot. 28, 477-478. Ogata, K., Ueda, K., Nagasawa, T., and Tani, Y. (1974). J. Antibiot. 27, 343-345. Okura, A,, Morishima, H., Takita, T., Aoyagi, T., Takeuchi, T., and Umezawa, H. (1975). J. Antibiot. 28, 337439. O'Reilly, R. A. (1975). Ann. Intern. Med. 83, 506-508. Perlman, D., and Peruzzotti, G. P. (1970). Adu. Appl. Microbial. 12, 277-294. Phansalkar, A. G., and Balwani, J. H. (1970). Hind. Antibiot. BuU. 12, 179-181. Pitkin, R. M., and Reynolds, W. A. (1970). Diabetes 19, 8590. Polson, J. B., and Wosilait, W. D. (1969). Proc. SOC. E x p . Biol. Med. 132, 963-967. Russell, J. T., Hansen, E. L., and Thorn, N. A. (1974). Acta Endom'nol. (Copenhagen) 77, 44-50, Samuel, P., Holtzman, C. M., and Meilman, E. (1973). Circ. Res. 33, 393-402. Sasaki, H., Hosokawa, T., Sawada, M., and Ando, K. (1973). J. Antibiot. 26, 67-80, Sawada, M., Hosokawa, T., Okutomi, T., and Ando, K. (1973). J. Antibiot. 26, 681486. Schein, P. S., and Bates, R. W. (1968). Diabetes 17, 760-765. Schwartz, A., Lewis, R., Hanley, H . G., Munson, R. G., Dial, F. D., and Ray, M. V. (1974). Circ. Res. 34, 102-111. Takeuchi, T., Ogawa, K., Iinuma, H., Suda, H., Ukita, K., Nagatsu, T., Kato, M., and Umezawa, H. (1973). J. Antibiot. 26, 162-167. Thoa, N. B., Costa, J. L., Moss, J., and Kopin, I. J. (1974). Lije Sci. 14, 1705-1719. Timmermans, L. (1974). J . Urol. 112, 348-349. Triggle, C. R., Grant, W. F., and Triggle, D. J. (1975). J . P ~ Q T - T M Z C194, O ~ .182-190. Umezawa, H., Takeuchi, T., Iinuma, H., Suzuki, K . , Ito, M., and Matsuzaki, M. (1970). J. Antibiot. 23, 514-518. Umezawa, H., Iinuma, H., Ito, M., Matsuzaki, M., and Takeuchi, T. (1972). J . Antibiot. 25, 239-242.

Umezawa, H., Aoyagi, T., Okura, A., Morishima, H., Takeuchi, T., and Okami, (1973). /. Antibiot. 26, 787-789. Van den Bosch, J. F., and Claes, P. J. (1967). Frog. Biochem. Phannacol. 2, 97-104. Van der Plas, P. M., Kraan, L., van Es, G., Stibbe, J., and Hemker, H. C. (1974). Huemostusis 3, 1-7. Velerninsky, J., Burr, I. M., and Stauffacher, W. (1970). Eur. J. Clin. Inuest. 1, 1W108. Wakabayashi, K., and Yamada, S. (1972). Jpn. J . Phurmacol. 23, 7-07, White, J. G., Rao, G. H., and Gerrard, J. N. (1974). Am. J. Patho[. 77, 135-149. Wingender, W., von Hugo, H., and Frommer, W. (1975). I. Antibiot. 28, 611. Woods, S. C., Hutton, R. A,, and Makous, W. (1970). Proc. SOC. E r p . B i d . Med. 133, -968. Wyse, B. M., and Dulin, W. E. (1971). Proc. SOC. Exp. B i d . Med. 136, 70-72.

SUBJECT INDEX

Antihypertensive substances from microorganisms, 269 Antiinflammatory substances from microorganisms, 269 Antimycoin A, 5, 33 Antipain, 277 Antipiriculin, 61 Ascofuranol, 285 Ascofuranone, 285 Ascosin, 2, 9, 12, 25 Aurenin, 6 Aureofacin, 9 Aureofungin, 9, 12, 25 Aureothricin, 61 Avenomycin, 13 Axenomycins, 3 Azacolutin (F-17-C), 9, 12, 25

A

Aabomycin A, 82 Actinomycin D, 272 Actinophenol, 45 Adriamycin, 270 Aeromycin B, 4 Akitamycin (toyamycin), 5 Alamethicin, 275, 276 Albotetraene, 5 Aliomycin, 7 Alkinonase A, 277 Alkinonase AF, 277 Alkyl arsines, 191, 195 Amethylfungimycin, 26 Aminomycin, 10 Aminosidin, 279 Amphotericin A, 5 Amphotericin B, 13, 22, 27, 28, 33, 38, 43, 44 Ampicillin, 279 Anisomycin, 80 Antibiotics 0371, 7 17-41 B, 7 A-3, 11 A-228, 7 A-1404, 9 A-5283, 6 A23187, 270, 271, 272, 274, 279, 281 AC435, 6 HA-106, 6 HA-135, 7 HA-145, 7 HA-176, 7 J4-B. 6 LIA 0777, 6 MM-8, 4 PA-153, 7 PA-166, 4 RP-7071, 6 RP-9971, 5 x-63, 11 Antiblastin, 61 Antifungin 4915, 9

B

Bacitmcin, 277 Bihoromycin, 82 Biological methylation, 189 Blasticidin A, 61 Blasticidln S, 54, 56, 62, 63,64, 65, 66, 81 Blastmycin, 61 C

Cabicidin, 6 Candicidm, 286 Candicidin (G-252, PA-150), 2, 9, 12, 15, 16, 17, 19, 22, 24, 25, 26, 27, 28, 29, 30, 32, a34 Candidin, 10, 13, 15, 28, 34, 35, 38, 40 Candidinin, 10 Candihexin, 15, 35, 38, 40, 44, 45 Candihexin A,B, 8 Candihexin E , F , 8 Candimycin, 10, 12, 25 Capacidm, 7 Cardiotonic substances from fermentations, 269 Cellocidin

289

290

SUBJECT INDEX

Cephalosporin acetylesterase, 115 Cephalosporin acylases, 114 Cephalosporins, 90, 92, 96 Cephamycins, 92 Cerulenin, 26 Chainin, 6, 13 Chloramphenicol, 55, 57, 59, 279 Cholesterol-amphotericin B, 40 Cholesterol-levorin. 40 Chromin, 5 tram-Cinnamic acid amide, 273 Citrinin, 82 Colistin, 277 Cryptocidin, 8 Cycloheximide, 42, 45, 55, 56, 59, 272 D

Daunoniycin, 270 Dermostatin (viridohlvin), 9, 13 Detoxin, 65 Diabetogenic agents from microorganisms, 269 Dicloxicillin, 278 Dienes, 3 4,6-Dimethoxyisoflavone, 273 4,8-Dimethoxyisoflavone, 273 Dimethylarsenic acid, 215 Dimethylselenide, 191 Dimethyltelluride, 191 Distamycin C, 7 Distreptomycin, 284 Dopastin, 273 E

Elastatinal, 277 Endomycin A (helixin A), 5 Endomycin B (helixin B), 8 Erythromycin, 271, 278 Etruscomycin, 4, 13 Eurocidin A, 71, 13, 61 Eurocidin B, 7, 13, 61 Ezomycin, 57, 79

Flavoviridomycin, 5 Fradicin, 8 Fumagillin, 39 Furnanornycin, 7 Fungichromatin, 67 Fungichromin, 2, 6, 13, 22 Fungicidin, 5, 13, 38, 41, 42 Fungimycin, 10, 12, 17 0

Gangtokumycin, 7 Genimycin, 8 Gentamicin, 277, 279 Gerobrecin, 9 Gramicidin A, 275, 276 Griseofulvin, 55, 56, 60 Grubilin. 11

ti Hamycin, 2, 9, 12, 25, 286 Harman, 273 Hepcin, 11 Heptaenes, 3, 9, 11 DJ-400 B,, 10, 12, 13, 25 DJ-400 Bt, 10, 12, 13, 25 Eurotin A, 9 Sch 16656, 10, 12, 14, 25 Heptafungin A, 9 Heptamycin, 11, 12, 25 Hexaenes, 3, 8 Hexin, 8 Hygroscopin, 61 Hypocholestolemic agents from microorganisms, 269 I

Isoxazidyl penicillins, 279 K

Kanamycin, 277 Kasugamycin, 54, 56, 62, 66, 67, 68, 69 Kinonase. 277

F

L

Filipin, 22, 39, 274 Filipin complex (durhamycin), 6, 13 Flavacid, 8 Flavofungin (mycoticin A), 2, 8, 13 Flavomycoin, 2, 8

Lagosin, 2, 6, 13 Lasalocid, 270, 272 Laurusin, 82 Leucensomycin, 4, 13

SUBJECT INDEX

Leucomycin, 271 Leupeptins. 275 Levorin &, A,, A2, As, B(26/1), 2, 9, 12, 25, 28, 36, 37, 40, 42, 43, 44, 45, 46 Levoristatin, 43, 44 M

Mediocidm, 8 Mercury methylation, 197 Methylmercury, 190, 192, 196, 214, 216 Methylspinazarin, 273 7-0-Methylspinochrome B, 273 Miharamycin, 82 Milbemycins, 80 Moldicidin A, 7 Moldicidin B, 6, 13 Monicamycin, 11 Mycelin, 8 Mycelin IMO, 9 Mycoheptin (2814 H), 10, 13, 28, 36, 42 Mycoticin B, 2, 8, 13 Mycotrienin, 4 N

Neoheptane, 11 Neomycin, 277, 285 N-acetylated, 284 dimethylaminopropylneomycin, 284 N-hexaacetylneomycin, 283 N-methylated neomycin, 283, 284 Neopentaene. 6 Neuramidase, 228, 229, 231, 232, 233, 239, 243, 244, 250, 251 Neuromuscular blockade, 269 Nogalamycin, 272 Novobiocin, 57, 60 Nursimycin, 11 Nystatin A,, Az, A3, 2, 5, 13, 27, 28, 29, 35, 38, 39, 42, 43, 44, 45 0

Oleandomycin, 271 Onomycin I, 7 Oosponol, 273 Ornamycin (17731), 5 Oudenone, 273 Oxytetracycline, 55

29 1 P

Penicillin acylase, 97, 99, 101, 105, 110, 111 G acylase, 108 V acylase, 108 acyltransferases, 108, 111 transacylase, 111 Pentaenes, 3, 6 G-8, 7 Glaxo-A246, 6 Pentafungin, 7 Pentamycin, 6, 13, 61 Pentaneucin, 6 Perimycin, 12 Perimycin (NC-968), 10, 12, 25 Phenethylamiue, 273 Phenopicolinic acid, 273 Photosynthetic bacteria, 163, 166 Photosynthetic SCP process, 172 Pimaricin (tennecetin), 2, 4, 13, 39 Pimprimine, 273 Pioticin, 14 Plumbomycin A, 5 Plumbomycin B, 5 Polifungin, 5, 13, 19, 38, 45 Polifungin A, 2 Polymyxin B, 277 Polyoxins, 54, 55, 56, 69, 70, 71, 72 Proteinases as pharmacological agents alkaline A and B, 277 neutral, 277 semi-alkaline, 277 Protocidin, 5 Puromycin, 272 Q

Quinquamycin, 7 R

Resistaphyllin, 4 Retikinonase I, 277 Rhizopchin, 14 Rifampin, 275, 278 Rimocidin (PA-%), 5, 13, 39 Rubrochlorine. 6 S

Shikimic acid, 26 Sialic acid, 231, 232, 235

292

SUBJECT INDEX

Sialoglycoprotein, 235, 237 Sialolipids, 236 Sistomycosin, 5 Spiramycin, 271, 279 Streptomycin, 55, 57, 58, 59, 277, 284, 286 Streptozotocin, 281, 282 Surgomycin, 8

Thiorhodaceae, 164 Toyokamycin, 80 Trichomycin A,B, 2, 3, 10, 12, 25, 43, 44, 61 Triene, 3, 4 Trienine, 4 Tristreptomycin, 284 U

T

Unamycin A, 6 Takamycin, 11 Tblimycin, 11 Tetraenes, 3, 4 Tetraenin A,B, 5 Tetrahexin, 8 Tetramedyn, 5 Tetramethyllead, 191 Tetramycin, 4 Tetramycoin A,B, 5 Tetranactin, 57, 62, 76, 77, 78 Tetrin A,B, 4, 13

V

Validamycin, 54, 57, 62, 73, 74, 75, 76 Valinomycin, 275, 276, 281 Viomycin, 277 Vitamin B,*, 167 X

Xantholycin B, 6

CONTENTS OF PREVIOUS VOLUMES Volume 1

Aerosol Samplers Harold W . Batchelor

Protected Fermentation

A Commentary on Microbiological Assaying

Miloi HeroEd and Jan NeEasek

F . Kauanagh

The Mechanism of Penicillin Biosynthesis

Application of Membrane Filters

Arnold L. Demain

Richard Ehrlich

Preservation of Foods and Drugs by Ionizing Radiations W . Dexter Bellamy

Microbial Control Methods in the Brewery

Gerhard

1. Hass

Newer Development in Vinegar Manufactures Rudolph J. Allgeier and Frank M . Hilde-

The State of Antibiotics in Plant Disease Control

David Pramer

brandt

Microbial Synthesis of Cohamides

The Microbiological Transformation of Steroids

D. Perlman

T.H . Stoudt

Factors Affecting the Antimicrobial Activity of Phenols E. 0. Bennett

Biological Transformation of Solar Energy William J . Oswald and Clarence 6 .

Golueke

Germfree Animal Techniques and Their Applications

SYMPOSIUM ON ENGINEERING hVANCES FERMENTATION PRACTICE

Arthur W . Phillips and lames E . Smith Insect Microbiology

Rheological Broths

S . R. Dutky The Production of Amino Acids by Fermentation Processes

Shukuo Kinoshita

Fred .'

Properties

of

Fermentation

Deindoerfer and John M . West

Fluid Mixing in Fermentation Processes

1. Y. Oldshue

Continuous Industrial Fermentations Philip Gerhardt and M . C . Bartlett

Scale-up of Submerged Fermentations W . H . Bartholemew

The Large-Scale Growth of Higher Fungi Radclqfe F . Robinson and R. S . Daoidson

Air

AUTHOR INDEX-SUBJECT

IN

INDEX

Volume 2

Newer Aspects of Waste Treatment Nandor Parges

Arthur E , Humphrey Sterilization of Media for Biochemical Processes

Lloyd L. Kempe Fermentation Kinetics and Model Processes

Fred H . Deindoerfer 293

294

CONTENTS OF PREVIOUS VOLUMES

volume 4

Continuous Fermentation W. D . Maxon Control Applications in Fermentation George 1. Fuld AUTHOR INDEX-SUBJECT

INDEX

volume 3

Preservation of Bacteria by Lyophilization Robert]. Heckly

Induced Mutagenesis in the Selection of Microorganisms S . I. Alikhanian The Importance of Bacterial Viruses in Industrial Processes, Especially in the Dairy Industry F . 1. Babel Applied Microbiology in Animal Nutrition Harlow H . Hall

Sphaerotilus, Its Nature and Economic Significance Norman C. Dondero

Biological Aspects of Continuous Cultivation of Microorganisms T . Holme

Large-Scale Use of Animal Cell Cultures Donald]. Merchant and C. Richard Eidam

Maintenance and Loss in Tissue Culture of Specific Cell Characteristics Charles C. Morris

Protection Against Infection in the Microbiological Laboratory: Devices and Procedures Mark A . Chatigny Oxidation of Aromatic Compounds by Bacteria Martin H . Rogoff Screening for and Biological Characterizations of Antitumor Agents Using Microorganisms Frank M . Schabel, Jr., and Robert F . Fittillo The Classification of Actinomycetes in Relation to Their Antibiotic Activity Elio Baldacci The Metabolism of Cardiac Lactones by Microorganisms Elwood Titus Intermediary Metabolism and Antibiotic Synthesis J. D . Bu’Lock Methods for the Determination of Organic Acids A. C . Hulme AUTHOR INDEX-SUBJECT

INDEX

Submerged Growth of Plant Cells L. G. Nickell AUTHOR INDEX-SUBJECT INDEX

Volume 5

Correlations between Microbiological Morphology and the Chemistry of Biocides Adrian Albert Generation of Electricity by Microbial Action J . B . Davis Microorganisms and the Molecular Biology of Cancer G. F. Gause Rapid Microbiological Determinations with Radioisotopes Gilbert V. Levin The Present Status of the 2,3-Butylene Glycol Fermentation Sterling K . Long and Roger Patrick Aeration in the Laboratory W. R. Lockhart and R. W. Squires

CONTENTS OF PREVIOUS VOLUMES

295

Stability and Degeneration of Microbial Cultures on Repeated Transfer Fritz Reusser

Biodegradation: Problems of Molecular Recalcitrance and Microbial Fallibility M . Alexander

Microbiology of Paint Films Richard T. Ross

Cold Sterilization Techniques John B . Opfell and Curtis E . Miller

The Actinomycetes and Their Antibiotics Selman A. Waksman

Microbial Production of Metal-rganic pounds and Complexes D.Perlman

Fuse1 Oil A. Dinsmoor Webb and John L. Zngraham AUTHOR INDEX-SUBJECT INDEX

Com-

Development of Coding Schemes for Microbial Taxonomy S . T . Cowan

Volume 6

Effects of Microbes on Germfree Animals Thomas D . Luckey

Global Impacts of Applied Microbiology: An Appraisal Carl-G&an Hede'n and Mortimer P. Starr

Uses and Products of Yeasts and Yeast-like Fungi Walter J. Nickerson and Robert 6 . Brown

Microbial Processes for Preparation of Radioactive Compounds D. Perlman, A d s P. Bayan, and Nancy A. Giufie Secondary Factors in Fermentation Processes P. Margalith Nonmedical Uses of Antibiotics Herbert S . Goldberg

Microbial Amylases Walter W . Windish and Nagesh S . Mhatre The Microbiology of Freeze-Dried Foods Gerald J . Silverman and Samuel A. Goldblith Low-Temperature Microbiology Judith Farrell and A. H . Rose AUTHOR INDEX-SUBJECT INDEX

Microbial Aspects of Water Polhpon Control K . Wuhnnann

Volume 8

Microbial Formation and Degradation of Minerals Melvin P. Siloennan and Henry L. Ehrlich

Industrial Fermentations and Their Relations to Regulatory Mechanisms Arnold L. Demain

Enzymes and Their Applications Zrwin W. Sizer

Genetics in Applied Microbiology S . G. Bradley

A Discussion of the Training of Applied Mi-

Microbial Ecology and Applied Microbiology Thomas D. Brock

crobiologists B. W .Koft and Wayne W . Umbreit AUTHOR INDEX-SUBJECT INDEX

Volume 7

Microbial Carotenogenesis Alex Ciegler

The Ecological Approach to the Study of Activated Sludge Wesley 0. Pipes Control of Bacteria in Nondomestic Water Supplies Cecil W . Chambers and Norman A. Clarke

296

CONTENTS OF PREVIOUS VOLUMES

The Presence of Human Enteric Viruses in Sewage and Their Removal by Conventional Sewage Treatment Methods Stephen Alan Kollins

Malo-lactic Fermentation Ralph E. Kunkee

Oral Microbiology Heiner Hoffman

Volume 10

Media and Methods for Isolation and Enumeration of the Enterococci Paul A. Hartman, George W .Reinbold, and Devi S. Saraswat Crystal-Forming Bacteria as Insect Pathogens Martin H . Rogoff Mycotoxins in Feeds and Foods Emanuel Borker, Nino F . Insalata, Colette P. k o i , a n d l o h n S . Witzeman AUTHOR INDEX-SUBJECT

INDEX

AUTHOR INDEX-SUBJECT

INDEX

Detection of Life in Soil on Earth and Other Planets. Introductory Remarks Robert L. Starkey For What Shall We Search? Allan H . Brown Relevance of Soil Microbiology to Search for Life on Other Planets 6 . Stotzky Experiments and Instrumentation for Extraterrestrial Life Detection Gilbert V . L o i n Halophilic Bacteria D . 1. Kushner

Volume 9

The Inclusion of Antimicrobial Agents in Pharmaceutical Products A. D. Russell, June Ienkins, and 1. H . Harrison Antiserum Production in Experimental Animals Richard M . Hyde Microbial Models of Tumor Metabolism G . F . Gause Cellulose and Cellulolysis Brigitta Norkrans Microbiological Aspects of the Formation and Degradation of Cellulose Fibers L. Iuraiek, I. Ross Coluin, and D. R. Whitaker

Applied Significance of Polyvalent Bacteriophages S. G . Bradley Proteins and Enzymes as Taxonomic Tools Edward D. Garber and John W . Rippon Mycotoxins Alex Ciegler and Eioind B . Lillehoj Transformation of Organic Compounds by Fungal Spores Claude Vbzina, S. N . Sehgal, and Kartar Singh Microbial Interactions in Continuous Culture Henry R. Bungay, I l l and Mary Lou Bungay Chemical Sterilizers (Chemosterilizers) Paul M . Borick

The Biotransformation of Lignin to HumuFacts and Postulates R. T. Oglesby, R. F. Christman, and C . H . Driver

AUTHOR INDEX-SUBJECT INDEX

Bulking of Activated Sludge Wesley 0. Pipes

CUMULATIVE AUTHOR INDEX~UMULATIVE TITLE INDEX

Antibiotics in the Control of Plant Pathogens M . J . Thirurnalachar

297

CONTENTS OF PREVIOUS VOLUMES

Volume 11

Collection of Microbial Cells Daniel I . C . Wang and Anthony]. Sinskey

Successes and Failures in the Search for Antibiotics Selman A . Waksman

Fermentor Design R. Steel and T . L. Miller

Structure-Activity Relationships of Semisyn. thetic Penicillins K . E. Price

The Occurrence, Chemistry, and Toxicology of the Microbial Peptide-Lactones A . Taylor

Resistance to Antimicrobial Agents J. S . Kiser, G. 0 . Gale, and G . A. Kemp

Microbial Metabolites as Potentially Useful Pharmacologically Active Agents D. Perlman and C. P . Peruzzotti

Micromonospora Taxonomy George Luedemunn

AUTHOR INDEX-SUBJECT INDEX

Dental Caries and Periodontal Disease Considered as Infectious Diseases William Gold The Recovery and Purlfication of Biochemicals Victor H . Edwards

Volume 13

Chemotaxonomic Relationships Among the Basidiomycetes Robert G. Benedict

Ergot Alkaloid Fermentations William J. Kelleher

Proton Magnetic Resonance SpectroscopyAn Aid in Identification and Chemotaxonomy of Yeasts P. A. J . Gorin and J. F . T . Spencer

The Microbiology of the Hen’s Egg R. G . Board

Large-Scale Cultivation of Mammalian Cells R. C . Telling and P. J . Radlett

Training for the Biochemical Industries I . L. Nepner

Large-Scale Bacteriophage Production K . Sargent

AUTHOR INDEX-SUBJECT INDEX

Microorganisms as Potential Sources of Food Jnanendra K . Bhattacharjee

Volume 12

History of the Development of a School of Biochemistry in the Faculty of Technology, University of Manchester Thomas Kennedy Walker Fermentation Processes Employed in Vitamin C Synthesis Milod Kulhanek Flavor and Microorganisms P. Margalith and Y . Schwartz Mechanisms of Thermal Injury in Nonspomlating Bacteria M . C. Allwood and A. D. Russell

Structure-Activity Relationships Semisynthetic Cephalosporins M. L. Sassiljer and Arthur Lewis

Among

Structure-Activity Relationships in the Tetracycline Series Robert K . Blackwood and Arthur R. English Microbial Production of Phenazines J. M . lngram and A. C . Blackwood The Gibberellin Fermentation E . G . ]ef&eys Metabolism of Acylanilide Herbicides Richard Bartha and David Pramer

298

CONTENTS OF PREVIOUS VOLUMES

Therapeutic Dentrifrices J . K . Peterson

Fermentation Equipment G . L. Solomons

Some Contributions of the U.S.Department of Agriculture to the Fermentation Industry GeorgeE. Ward

The Extracellular Accumulation of Metabolic Products by Hydrocarbon-Degrading Microorganisms Bernard J . Abbott and William E . Gledhill

Microbiological Patents in International Litigation John V. Whittenburg

AUTHOR INDEX-SUBJECT INDEX

Industrial Applications of Continuous Culture: Pharmaceutical Products and Other Products and Processes R. C . Righelato and R. Elsuxnth

Medical Applications of Microbial Enzymes I N i n W . Sizer

Mathematical Models for Fermentation Processes A. 6 . Frederickson, R. D. Megee, Ill, and H . M . Tsuchija AUTHOR INDEX-SUBJECT INDEX

Volume 14

Development of the Fermentation Industries in Great Britain John J . H. Hastings Chemical Composition as a Criterion in the Classification of Actinomycetes H. A . Lechevalier, M a y P. Lechevalier, and Nancy N. Gerber Prevalence and Distribution of AntibioticProducing Actinomycetes John N . Porter Biochemical Activities of Nocardia R. L. Raymond and V. W.Jamison Microbial Transformations of Antibiotics Oldrich K . Sebek and D. Perlmn

Volume 15

Immobilized Enzymes K . L. Smiley and G . W . Strandberg Microbial Rennets Joseph L. Sardinas Volatile Aroma Components of Wines and Other Fermented Beverages A. Dinsmoor W e b b and Carlos J . Muller Correlative Microbiological Assays Ladislav J . Harika Insect Tissue Culture W . F . Hink Metabolites from Animal and Plant Cell Culture Irving S. Johnson and George B . Boder Structure-Activity Relationships in Coumermycins John C . Godfiey and Kenneth E . Price Chloramphenicol Vedpal S . Malik Microbial Utilization of Methanol Charles L. Cooney and David W . Levine

In Vivo Evaluation of Antibacterial Chemotherapeutic Substances A. Kathrine Miller

Modeling of Growth Processes with Two Liquid Phases: A Review of Drop Phenomena, Mixing, and Growth P. S . Shah, L. T . Fan, 1. C . Kao, and L. E. Erickson

Modification of Lincomycin Barney J . Magerhn

Microbiology and Fermentations in the Prairie Regional Laboratory of the National

CONTENTS OF PREVIOUS VOLUMES

Research Council of Canada 19461971 R. H . Haskins AUTHOR INDEX-SUBJECT

299

Fungal Sterols and the Mode of Action of the Polyene Antibiotics J . M. T. Hamilton-Miller

INDEX

Volume 16

Public Health Significance of Feeding Low Levels of Antibiotics to Animals Thomas H . Jukes Intestinal Microbial Flora of the Pig R. Kenworthy Antimyciu A, a Piscicidal Antibiotic Robert E . Lennon and Claude Vbzina Ochratoxins Kenneth L. Applegate and John R. Chipley Cultivation of Animal Cells in Chemically Defined Media, A Review Kiyoshi Higuchi Genetic and Phenetic Classification of Bacteria R. R. Colwell Mutation and the Production of Secondary Metabolites Arnold L. Demain Structure-Activity Relationships in the Actinomycins Johannes Meienhofer and Eric Atherton Development of Applied Microbiology at the University of Wisconsin William B. Sarks

Methods of Numerical Taxonomy for Various Genera of Yeasts 1. Campbell Microbiology and Biochemistry of Soy Sauce Fermentation F . M . Young and B. J . B . Wood Contemporary Thoughts on Aspects of Applied Microbiology P. S . S . Dawson and K . L. Phillips Some Thoughts on the Microbiological Aspects of Brewing and Other Industries Utilizing Yeast G . 6. Stewart Linear Alkylbenzene Sulfonate: Biodegradation and Aquatic Interactions WilliamE . GledhiU The Story of the American Type Culture Collection-Its History and Development (1899-1973) WillinmA. Clark and Dorothy H . Geary Microbial Penicillin Acylases E . J . Vandamme a n d ] . P. Voets SUBJECT INDEX

Volume 18

Microbial Formation of Environmental Pollutants Martin Alexander

AUTHOR INDEX-SUBJECT INDEX

Volume 17

Microbial Transformation of Pesticides Jean-Marc Bollag

Education and Training in Applied Microbiology Wayne W. Umbreit

Taxonomic Criteria for Mycobacteria and Nocardiae S . G . Bradley and J . S . Bond

Antimetabolites from Microorganisms Daoid L. Pruess and James P. Scannell

Effect of Structural Modfications on the Biological Properties of Aminoglycoside Antibiotics Containing 2-Deoxystreptamine Kenneth E . Price, John C . Godfi-ey, and Hiroshi Kawaguchi

Lipid Composition as a Guide to the Classification of Bacteria Nwman Shaw

300

CONTENTS OF PREVIOUS VOLUMES

Recent Developments of Antibiotic Research and Classification of Antibiotics According- to Chemical Structure @nos B b d y

Effects of Toxicants on the Morphology and Fine Structure of Fungi Donald V. Richmond SUBJECT INDEX

SUBJECT INDEX

Volume 19

Culture Collections and Patent Depositions T . G. Pridham and C . W. Hesseltine Production of the Same Antibiotics by Members of Different Genera of Microorganisms Hubert A . Lechevalier Antibiotic-Producing Fungi: Current Status of Nomenclature C . W. Hesseltine and 1.J. Ellis Significance of Nucleic Acid Hybridization to Systematics of Actinomycetes S . G. Bradley Current Status of Nomenclature of AntibioticProducing Bacteria Erwin F . Lessel Microorganisms in Patent Disclosures lming Marcus Microbiological Control of Plant Pathogens Y. Henis and I . C h t Microbiology of Municipal Solid Waste Composting Melvin S. Finstein and Merry L. Morris

Nitrification and Deuitdcation Processes Related to Waste Water Treatment D . D. Focht and A. C . Chang The Fermentation Pilot Plant and Its Aims D. I. D. HockenhuU The Microbial Production of Nucleic Acid-Related Compounds Koichi Ogata Synthesis of L-Tyrosine-Related Amino Acids by @-Tyrosinase Hideaki Y a m & and Hidehiko Kumagai

Volume 20

The Current Status of Pertussis Vaccine: An Overview Charles R. Manclark Biologically Active Components and Properties of Bordetella pertussis Stephen I. Morse Role of the Genetics and Physiology of Bwdetella pertussis in the Production of Vaccine and the Study of Host-Parasite Relationships in Pertussis Charlotte Parker Problems Associated with the Development and Clinical Testing of an Improved Pertussis Vaccine George R. Anderson Problems Associated with the Control Testing of Pertussis Vaccine Jack Cameron Vinegar: Its History and Development Hubert A . Conner and Rudolph J . AUgeier Microbial Rennets M . Sternberg Biosynthesis of Cephalosporins Toshihiko Kanzaki and Yukio Fujisawa Preparation of Pharmaceutical Compounds by Immobilized Enzymes and Cells Bernard J. Abbott Cytotoxic and Antitumor Antibiotics Produced by Microorganisms

I . Fuska and B . Proksa SUBJECT INDEX

A

7

c D E F G H

9 0 l 2 3 4

-R R-

1 5 J 6