Natural Products

Contents

Contributors

Section I Natural Products in the Natural World

Part 1 Role and Reason

1 The Role of Phytochemicals in Relationships of Plants with Other Organisms

1.1 Introduction

1.2 Glucosinolates

1.2.1 Glucosinolates Affect Insect–Plant Relationship

1.2.2 Glucosinolates in Plant Immunity

1.3 Benzoxazinone Glucosides

1.4 Strigolactones

1.5 Phytoalexins – Inducible Defense Metabolites

1.5.1 Phenyalanine-derived Phytoalexins

1.5.2 Phytoalexins in Brassicaceae

1.6 Conclusions

References

2 Designer Microbial Ecosystems – Toward Biosynthesis with Engineered Microbial Consortia

2.1 Introduction

2.2 Bacterial Cell-to-Cell Communication via Quorum-Sensing Systems

2.3 Engineering Population Control into Designer Bioproduction Consortia

2.4 Control and Optimization of Bioproduction Consortia

2.5 Design of Synthetic Microbial Consortia for Biosynthesis

2.6 Conclusions

Acknowledgments

References

3 Marine Natural Products – Chemical Defense/Chemical Communication in Sponges and Corals

3.1 Introduction

3.2 Chemical Communication between the Organism and Its Environment

3.2.1 Feeding Deterrents

3.2.2 Compounds Inducing Larvae Settlement

3.2.3 Photoprotective and Antioxidant Compounds

3.2.4 Antifouling Compounds

3.2.5 Antimicrobial Compounds

3.3 Mediating Communication between Host and Microbial Associates

3.3.1 Chemical Control by the Host of Its Microbial Partners

3.3.2 Chemical Resistance of the Microbial Partners to the Host Digestion

3.3.3 Chemical Defense of the Host by Associated Microorganisms

3.4 Chemical Communication within the Host Microbial Compartment

3.4.1 Molecules Involved in Quorum Sensing

3.4.2 Molecules Involved in Bacterial Antagonisms

3.5 Conclusions and Perspectives

References

Part 2 Self-Protection – Avoiding Autotoxicity

4 How Plants Avoid the Toxicity of Self-Produced Defense Bioactive Compounds

4.1 Introduction

4.2 Sequestration and Excretion

4.2.1 Vacuolar Sequestration

4.2.2 Extracellular Excretion

4.3 Genomic Clustering

4.4 Target Mutation-based Mechanism

4.5 Predicting Drug Resistance in Other Organisms

Acknowledgments

References

Part 3 Fishing and Pharming

5 Marine Bioprospecting

5.1 Introduction

5.2 International Treaties and Permit Issues

5.3 Techniques and Types of Collection

5.4 Screening Extracts vs. Fractions vs. Compounds

5.5 Chemical and Biological Screening Methods

5.6 Innovations on the Horizon

5.7 Conclusions

Acknowledgments

References

6 Myxobacteria: Chemical Diversity and Screening Strategies

6.1 Introduction

6.2 Natural Products from Myxobacteria: Chemistry and Biological Activity, a Review of Publications Since 2009

6.2.1 Peptides

6.2.2 Macrolides

6.2.3 Polyketides

6.2.4 Miscellaneous

6.3 Screening for New Scaffolds

6.3.1 Screening for New Antimicrobials (Bioassay-Guided Fractionation)

6.3.2 Mining New Myxobacterial Taxa and Structure-Guided Isolation: The Aethearmides

6.3.3 Genome- and Metabolome-Mining: Myxoprincomide

6.4 Conclusions

Acknowledgment

References

7 Fungal Endophytes of Grasses and Morning Glories, and Their Bioprotective Alkaloids

7.1 Introduction

7.2 Taxonomy of Clavicipitaceae and Host Grasses

7.3 Symbiosis Growth, Fruiting, and Pathogenesis

7.4 Endobiotic, Epibiotic, and Ectobiotic Growth

7.5 Phylogenetic Relationships

7.6 Ergot Alkaloids

7.7 Indole-Diterpenes

7.8 Peramine

7.9 Loline Alkaloids

7.10 Conclusions

References

8 Fungal-Actinomycete Interactions – Wakening of Silent Fungal Secondary Metabolism Gene Clusters via Interorganismic Interactions

8.1 Introduction

8.2 Microbial Regulatory Interactions

8.3 Interorganismal Interaction and Chromatin-Based Gene Regulation

8.4 Conclusions

References

9 Secondary Metabolites Produced by Plant Pathogens

9.1 Introduction

9.2 Bacterial Secondary Metabolites and Plant Disease

9.3 Fungal Secondary Metabolites as Host-Selective Toxins

9.4 A Secondary Metabolite as a Fungal Avirulence Factor

9.5 Non-Host-Selective Toxins and Plant Disease

9.6 Secondary Metabolite Gene Clusters and Horizontal Gene Transfer

9.7 Secondary Metabolite Toxins as Protection Against Predation

9.8 Conclusions and Future Directions

Acknowledgments

References

Section II From Genes to Molecules

Part 1 Reading the Genome

10 Analyzing Fungal Secondary Metabolite Genes and Gene Clusters

10.1 Introduction

10.2 Tools for Bioinformatics Analyses of Fungal SM Biosynthetic Pathways

10.3 From Genes to Chemical Structures

10.3.1 Polyketide Synthases

10.3.2 Nonribosomal Peptide Synthetases

10.3.3 PKS-NRPS Hybrids

10.3.4 Terpenoids

10.3.5 Cooperation among Classes of Core SM Genes

10.4 Prospects

Acknowledgments

References

Part 2 Biosynthesis and Heterologous Expression

11 RiPPs: Ribosomally Synthesized and Posttranslationally Modified Peptides

11.1 Introduction

11.2 Lanthipeptides

11.2.1 Bioengineering Studies in Native Producers and Heterologous Hosts

11.2.2 In vivo engineering of lanthipeptides in E. coli

11.2.3 In vitro engineering of lanthipeptides

11.3 Linear Azol(in)e-Containing Peptides (LAPs)

11.4 Thiopeptides

11.5 Cyanobactins

11.6 Lasso Peptides

11.7 Microviridins

11.8 Sactipeptides: Peptides Crosslinked by Cys to a-Carbon Linkages

11.9 Summary and Outlook

References

12 Polyketide Synthase: Sequence, Structure, and Function

12.1 Introduction

12.2 Similarity and Differences between PKS and FAS

12.3 Sequence–Structure–Function Relationship of PKS Domains

12.3.1 Acyltransferase (AT)

12.3.2 Ketosynthase (KS)

12.3.3 Ketoreductase (KR)

12.3.4 Dehydratase (DH)

12.3.5 Enoylreductase (ER)

12.3.6 Aromatase/Cyclase (ARO/CYC)

12.3.7 Product Template Domain (PT)

12.3.8 Thioesterase (TE)

12.3.9 Acyl Carrier Protein (ACP)

12.4 ACP and Sequestration Hypothesis of FAS and PKS

12.5 Conclusion and Future Directions

References

13 Manipulation of Fungal Natural Product Pathways

13.1 Introduction

13.2 Precursor-Directed Biosynthesis and Mutasynthesis

13.3 Gene Knockout and Silencing

13.4 Heterologous Expression

13.5 Yeast Expression

13.6 Gene Cluster Expression

13.7 Epigenetic Remodeling

13.8 Perspective

References

14 Production of Therapeutic Products

14.1 Introduction

14.2 The Production Host and the Influence on Process Development

14.2.1 Genetic, Metabolic, and Process Engineering of the Natural Product Production Host

14.2.2 Current Production Routes: How Are Common Natural Products Produced?

14.3 Heterologous Natural Product Biosynthesis

14.4 Conclusions and Future Directions

References

Part 3 Regulation: Waking Sleeping Pathways

15 Waking Sleeping Pathways in Filamentous Fungi

15.1 Introduction

15.2 Discovery

15.3 One Strain Many Compounds

15.4 Interspecies Crosstalk

15.5 Molecular Manipulation

15.6 Epigenetic Manipulation

15.7 Heterologous Expression

15.8 Conclusions and Future Directions

References

Section III Evolving Enzymes, Evolving Pathways: Synthetic Biology

Part 1 Chemical Diversification

16 The Oxidosqualene Cyclases: One Substrate, Diverse Products

16.1 Introduction

16.2 Animal and Fungal Oxidosqualene Cyclases

16.3 Plant Oxidosqualene Cyclases

16.4 Bacterial Squalene Cyclases

16.5 Conclusions and Future Directions

References

17 Harnessing Sugar Biosynthesis and Glycosylation to Redesign Natural Products and to Increase Structural Diversity

17.1 Introduction

17.2 Deoxysugar Biosynthesis

17.3 Deoxysugar Transfer

17.4 Deoxysugar Modification

17.4.1 Altering the Glycosylation Pattern by Combinatorial Biosynthesis

17.5 In Vitro Glycorandomization

17.6 Conclusions and Prospects for the Future

Acknowledgments

References

Part 2 Evolving Pathways

18 Evolutionary Mechanisms Involved in Development of Fungal Secondary Metabolite Gene Clusters

18.1 Introduction

18.2 Complex Evolution of Fungal Secondary Metabolism Gene Clusters: Two Case Studies

18.2.1 Genetic Rearrangements within Aflatoxin and Related Gene Clusters

18.2.2 Evolution of the ACE1 Gene Cluster in Ascomycetes

18.2.3 Similar Mechanisms Occur in Other Secondary Metabolism Gene Clusters

18.3 Conclusion

References

Part 3 Synthetic Biology

19 Synthetic Biology of Natural Products

19.1 Introduction

19.2 Computer-Aided Pathway Engineering

19.2.1 Predicting Pathways to Produce Desired Compounds

19.2.2 Enzyme Design for Novel Chemistry

19.2.3 Computational Detection of Biosynthetic Units in Microbial Genomes

19.3 Rewriting the Genetic Code

19.3.1 Chemical Synthesis of Huge Gene Clusters

19.3.2 Rapid Assembly of Engineered Pathways

19.3.3 Synthesis of Entire Microbial Genomes

19.4 Designer Cell Factories for Natural Products

19.4.1 Transplantation of Production Pathways to Heterologous Hosts

19.4.2 Optimization of Heterologous Pathways for Overproduction

19.4.3 Refactoring of Natural Pathways for Facilitated Engineering

19.5 Future Perspectives

Acknowledgments

References

Section IV Screening for Bioactivity

20 Image-Based Screening Approaches to Natural Products Discovery

20.1 Introduction

20.1.1 Terms and Conventions

20.1.2 Methods in Image-Based Screening

20.1.3 Advantages of Image-Based Screening

20.1.4 Limitations of Image-Based Screening

20.1.5 Challenges for Natural Products Discovery

20.1.6 Opportunities in Natural Products Research

20.2 Applications of Image-Based Screening to NP Discovery

20.2.1 Mammalian Cells

20.2.2 Protozoan Parasites

20.2.3 Helminth Worms

20.2.4 Caenorhabditis elegans

20.2.5 Zebrafish

20.2.6 Bacteria and Viruses

20.3 Future Perspective

References

21 Making Sense of Structures by Utilizing Mother Natures Chemical Libraries as Leads to Potential Drugs

21.1 Introduction

21.1.1 Use of Privileged Structures with Multiple Activities

21.2 Antidepressant Agents from Dyestuff Intermediates

21.2.1 Synthesizing Natural Products, Ahead of Their Discovery from Nature

21.3 Benzopyrans, Unusual Antibacterial and Other Agents

21.4 A Selection of Other Privileged Structural Classes

21.5 Multiple Enzymatic Inhibitors from Relatively Simple Natural Product Secondary Metabolites

21.6 The “Inside-Out” Approach

21.7 Inhibitors of Protein–Protein Interactions

21.8 Underprivileged Scaffolds

21.9 Conclusion

References

22 Is There an Ideal Database for Natural Products Research?

22.1 Introduction

22.2 Requirements

22.3 Reality

22.3.1 Biogeography and Taxonomy

22.3.2 Dereplication

22.3.3 Characterization

22.3.4 Assessing Biological Potential

22.3.5 Searching the Databases

22.4 Selection of a Database for Natural Products Research

22.5 Future Directions

References

Section V To Application

Case Studies

23 Daptomycin and A54145: Structure–Activity Relationship (SAR) Studies Enabled by Combinatorial Biosynthesis

23.1 Introduction

23.2 Daptomycin and A54145

23.3 Combinatorial Biosynthesis Methodology

23.3.1 A21978C and A54145 Gene Clusters

23.3.2 Expression Hosts

23.3.3 Versatile Vectors and Combinatorial Design

23.3.4 Parts and Devices

23.4 Combinatorial Biosynthesis

23.4.1 Rules for Exchange of Functional Parts

23.4.2 Deletion of Genes Involved in Amino Acid Modifications

23.4.3 Combinatorial Exchanges to Improve Lipopeptide Properties

23.5 Genome Mining for Lipopeptide Biosynthetic Pathways

23.6 Conclusions and Perspectives

References

24 Discovery and Development of NVB302, a Semisynthetic Antibiotic for Treatment of Clostridium difficile Infection

24.1 Introduction

24.2 Lantibiotic Biosynthesis

24.3 Generation of Lantibiotic Libraries

24.4 Chemical Semisynthesis

24.5 Clostridium Difficile Infection

24.6 NVB302 for C. difficile Infection

24.6.1 In Vitro Microbiology

24.6.2 In Vivo Biology

24.6.3 Toxicology

24.6.4 Phase I Clinical Trial

References

25 ILS-920: A Rapamycin Analog for IschemicStroke

25.1 Introduction

25.2 Design of Nonimmunosuppressive Rapamycin Analogs

25.3 Pharmacokinetics and Brain Penetration of ILS-920

25.4 ILS-920 Provides Long-Term Functional Recovery Following Permanent Middle Cerebral Artery Occlusion

25.5 ILS-920 Promotes Survival of Multiple Brain Cell Types and Increases Immunohistochemical Markers of Regeneration Following MCAO

25.6 Summary

Acknowledgments

References

26 BC265: A Nonquinone Ansamycin Hsp90 Inhibitor Developed Using Biosynthetic Medicinal Chemistry

26.1 Introduction

26.2 Next Generation Ansamycin Polyketide Hsp90 Inhibitors

26.3 Rational Bioengineering of the Macbecin Biosynthetic Gene Cluster

26.4 BC265 Is a Potent Inhibitor of Hsp90

26.5 BC265 Exhibits an Improved Safety and Efficacy Profile

26.6 Summary

Acknowledgments

References

27 Discovery and Development of Caspofungin (CANCIDAS): Concept to Clinic

27.1 Introduction

27.1.1 Background and Rationale

27.2 Discovery of Natural Product Lead

27.2.1 Pneumocandin B0 Structure Determination

27.2.2 Pneumocandin B0 Purification

27.3 Fermentation Development of Pneumocandin B0: The Ultimate Lead for Making Caspofungin

27.3.1 Titer Improvement

27.4 Chemical Optimization of Pneumocandin B0 and Selection of the Preclinical Candidate

27.4.1 Efforts to Enhance the Solubility and Stability of Pneumocandin B0

27.4.2 From Lab to Patient: Development of API and Formulation Manufacturing Processes for CANCIDAS

27.5 Clinical Development of Caspofungin

References

Index

Supplemental Images