Genetics and Biochemistry of Antibiotic Production

Edited by

Leo C. Vining and Colin Stuttard

Dalhousie University Halifax, Nova Scotia, Canada

Butterworth-Heinemann Boston London Oxford Singapore Sydney Toronto Wellington CONTENTS

Preface xxi

SECTION A. GENETIC AND ENVIRONMENTAL CONTROL OF ANTIBIOTIC PRODUCTION 1 Overview by Leo C Vining

1. Global Physiological Controls 9 Janice L. Doull and Leo C. Vining 1.1 Introduction 9 1.2 Regulatory Mechanisms 11 1.3 Operation of Global Control Systems 30 1.4 Global Control of Secondary Metabolism 40 References 54

2. Genetics of Antibiotic Production in Streptomyces coelicolor A3(2), a Model Streptomycete 65 David A. Hopwood, Keith F. Chater and Mervyn J. Bibb 2.1 Introduction 65 2.2 The Pathway Genes 69 2.3 Transition from Primary to Secondary Metabolism 85 2.4 Genes with Pleiotropic Effects on the Production of Antibiotics 87 2.5 Conclusion 96 References 97

xm xiv Contents

3. Autoregulators 103 Sueharu Horinouchi and Teruhiko Beppu 3.1 Introduction 103 3.2 Streptomycete Autoregulators 104 3.3 Genetics of A-Factor Biosynthesis 110 3.4 Binding Proteins 111 3.5 Regulatory Cascade for Streptomycin Biosynthesis 113 3.6 A Model for Regulation of Streptomycin Biosynthesis 115 3.7 Conclusions 117 References 118

SECTION B. PEPTIDE AND PEPTIDE-DERIVED ANTIBIOTICS 121 Overview by Leo C. Vining and Hans von Dohren

4. Peptides 129 Hans von Dohren 4.1 Introduction 129 4.2 Overview of Peptides from Bacilli 130 4.3 Genetics of Peptide Biosynthesis 133 4.4 Other Systems in Perspective 145 4.5 Regulatory Mechanisms in Peptide Producers 154 4.6 Enzymology of Peptide Biosynthesis 157 4.7 Towards the Design of Enzyme Systems 160 4.8 Summary 161 References 161

5. Peptidolactones 173 Ullrich Keller 5.1 Introduction 173 5.2 Biosynthesis of Acyl Peptidolactones 174 5.3 Aromatic Carboxylic Acid Activating Enzymes 177 5.4 Chromopeptidolactone Synthetases 183 5.5 Biosynthesis of Nonacyl Peptidolactones 188 5.6 Conclusions 192 References 193

6. Bialaphos 197 Charles J. Thompson and Haruo Seto 6.1 Introduction 197 Contents xv

6.2 Origin of the BA Carbon Skeleton 200 6.3 Biosynthesis via Phosphonopyruvate 200 6.4 Regulation 214 6.5 Resistance 215 6.6 Conservation of the BA Biosynthesis Genes 217 6.7 Implications for Metabolic Pathway Evolution 218 References 219

7. Thiopeptides 223 William R. Strohl and Heinz-Gunter Floss 7.1 Introduction 223 7.2 Biochemistry of Thiopeptides 225 7.3 Genetics of Resistance and Biosynthesis 231 7.4 Thiopeptide Resistance Genes in S. azureus 234 References 236

8. Beta-Lactams 239 Susan E. Jensen and Arnold L. Demain 8.1 Introduction 239 8.2 Penicillins, Cephalosporins and Cephamycins 240 8.3 Clavulanic Acid 250 8.4 Carbapenems 252 8.5 Monocyclic /3-Lactams 253 8.6 Regulation of /3-Lactam Biosynthesis 254 References 260

9. Glycopeptides 269 Milton J. Zmijewski, Jr. and Jeffrey T. Fayerman 9.1 Introduction 269 9.2 Genetics and Molecular Biology 270 9.3 Resistance 272 9.4 Biosynthesis 273 9.5 Concluding Remarks 279 References 279

10. Lantibiotics 283 Michael J. Gasson 10.1 Introduction 283 10.2 Lantibiotic Structures 285 10.3 Biosynthesis of Lantibiotics 288 10.4 Lantibiotic Biosynthesis Gene Organization 296 10.5 Genetic Elements Encoding Lantibiotic Genes 298 xvi Contents

10.6 Protein-engineered Lantibiotics 299 10.7 Lantibiotic Mode of Action 302 10.8 Concluding Remarks 302 References 303

11. Microcins 307 Felipe Moreno, Jose Luis San Milldn, Conception Herndndez-Chico and Roberto Kolter 11.1 Introduction 307 11.2 Discovery of Microcins 308 11.3 Microcins A, D and E 309 11.4 Microcins C and H 310 11.5 MicrocinB 311 11.6 ColicinV 313 11.7 Transcriptional Regulation 315 11.8 Chromosomal Microcin Genes in E. coli 315 11.9 Concluding Remarks 317 References 319

SECTION C. POLYKETIDE-DERIVED ANTIBIOTICS 323 Overview by Leo C. Vining and David A. Hopwood

12. Anthracyclines 331 C. Richard Hutchinson 12.1 Introduction 331 12.2 Discovery 332 12.3 Biological Activity 332 12.4 Fermentation 334 12.5 Biosynthesis 334 12.6 Genetics of Anthracycline Production 339 12.7 Production of New Anthracyclines 352 References 353

13. Tetracyclines 359 Vladislav Behal and Iain S. Hunter 13.1 Introduction 359 13.2 Biogenesis 360 13.3 Enzymes of Secondary Metabolism 361 13.4 Enzymes of Primary Metabolism 365 13.5 Cellular Location of Enzymes 366 13.6 Genetics and Molecular Genetics 366 Contents xvii

13.7 Regulation of Biosynthesis 374 13.8 Regulatory Mechanisms in the Mycelium 378 13.9 Supply of Antibiotic Precursors 379 13.10 Fermentation Analyses and Modelling 379 13.11 Production by Immobilized Cells 380 References 380

14. Macrolides 385 Leonard Katz and Stefano Donadio 14.1 Introduction 385 14.2 Cloning of Macrolide Biosynthesis Genes 387 14.3 Macrocyclic Lactone "Polyketide Synthases" 392 14.4 Modification of the Lactone Ring 403 14.5 Biosynthesis and Modification of Sugars 406 14.6 Resistance 410 14.7 Regulation 412 14.8 Future Prospects 413 References 415

15. Avermectins 421 Douglas J. MacNeil 15.1 Introduction 421 15.2 Biosynthesis 423 15.3 Genetics of Avermectin Biosynthesis 427 15.4 Conclusions 439 References 440

16. Polyethers 443 Ashley W. Birch and John A. Robinson 16.1 Introduction 443 16.2 Biochemical Aspects of Polyether Biosynthesis 445 16.3 Genetics of Polyether Biosynthesis 465 References 472

17. Ansamycins 477 JuiShen Chiao, TianHui Xia, BaiGen Mei, ZhiKun Jin and WeiLing Gu 17.1 Introduction 477 17.2 Organisms Producing Ansamycins 478 17.3 Rifamycin Biosynthesis 480 17.4 Regulation of Rifamycin and Macbecin Biosynthesis 484 17.5 Shikimate Pathway Regulation 484 17.6 Nitrogen Incorporation into Rifamycin 487 Contents

\1.1 Nitrogen Assimilation 488 17.8 Nitrogen Control of Rifamycin Production 489 17.9 Effects of Inorganic Phosphate 492 17.10 Effect of B-Factor on Rifamycin Biosynthesis 493 17.11 Genetics of Rifamycin Biosynthesis 493 References 494

SECTION D. OTHER BIOSYNTHETIC GROUPS OF ANTIBIOTICS 4" Overview by Leo C. Vining

18. Chloramphenicol 505 Leo C. Vining and Colin Stuttard 18.1 Introduction 505 18.2 Biosynthesis 507 18.3 Genetics 512 18.4 Physiological Regulation 515 18.5 Resistance 523 References 527

19. Streptomycin and Related Aminoglycosides 531 Wolfgang Piepersberg 19.1 Introduction 531 19.2 Streptomycin: Occurrence and Biology 532 19.3 Biosynthesis in 5. griseus 534 19.4 Cloning and Analysis of str Genes 541 19.5 Regulation of Streptomycin Production Genes 553 19.6 Conclusions and Perspectives 561 References 562

20. Aminoglycosides and Aminocyclitols 571 Kunimoto Hotta, Julian Davies and Morimasa Yagisawa 20.1 Introduction 571 20.2 AGACs Isolated since 1981 573 20.3 Butirosin 578 20.4 Semisynthetic AGACs 579 20.5 Biosynthesis of the Astromicin (Fortimicin) Group 581 20.6 AGAC Resistance Genes other than Self-resistance Genes 586 20.7 Gene Cloning in Micromonospora Species 590 20.8 Concluding Remarks 592 Contents xix

References 592

21. Polyoxins and Related Nucleosides 597 Kiyoshi Isono 21.1 Introduction 597 21.2 Polyoxins 598 21.3 Nikkomycins (Neopolyoxins) 607 21.4 PolyoxinN 611 21.5 Blasticidin S and Mildiomycin 611 21.6 Other Nucleoside Antibiotics Related to Polyoxins 614 21.7 Conclusions 614 References 615

22. Agrocins 619 Bruce G. Clare 22.1 Introduction 619 22.2 Agrobacterium species and Biovars 620 22.3 Agrocins: Chemistry, Bioactivity and Specificity 620 22.4 Agrocins: Genetics of Biosynthesis 623 22.5 Agrocins: Biochemistry and Biosynthesis 625 22.6 Agrocins and Agrocinopines: Genetics of Sensitivity 625 22.7 Agrocins: Biological Control 627 22.8 Conclusions 630 References 630

23. Isoprenoid Antibiotics 633 David E. Cane 23.1 Introduction 633 23.2 Isoprenoid Chain-elongation Enzymes 635 23.3 Sesquiterpene Synthases 642 23.4 What Next ? 649 References 651

Index 657