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Cover image: Courtesy of Joe Zarins-Tutt
Cover design by Nicole Teut

CONTENTS

Contributors

SECTION I NATURAL PRODUCTS IN THE NATURAL WORLD

Part 1 Role and Reason
1. 1 The Role of Phytochemicals in Relationships of Plants with Other Organisms
  1. 1.1 Introduction
  2. 1.2 Glucosinolates
  3. 1.3 Benzoxazinone Glucosides
  4. 1.4 Strigolactones
  5. 1.5 Phytoalexins – Inducible Defense Metabolites
  6. 1.6 Conclusions
  7. References
2. 2 Designer Microbial Ecosystems – Toward Biosynthesis with Engineered Microbial Consortia
  1. 2.1 Introduction
  2. 2.2 Bacterial Cell-to-Cell Communication via Quorum-Sensing Systems
  3. 2.3 Engineering Population Control into Designer Bioproduction Consortia
  4. 2.4 Control and Optimization of Bioproduction Consortia
  5. 2.5 Design of Synthetic Microbial Consortia for Biosynthesis
  6. 2.6 Conclusions
  7. Acknowledgments
  8. References
3. 3 Marine Natural Products – Chemical Defense/Chemical Communication in Sponges and Corals
  1. 3.1 Introduction
  2. 3.2 Chemical Communication between the Organism and Its Environment
  3. 3.3 Mediating Communication between Host and Microbial Associates
  4. 3.4 Chemical Communication within the Host Microbial Compartment
  5. 3.5 Conclusions and Perspectives
  6. References
Part 2 Self-Protection — Avoiding Autotoxicity
1. 4 How Plants Avoid the Toxicity of Self-Produced Defense Bioactive Compounds
  1. 4.1 Introduction
  2. 4.2 Sequestration and Excretion
  3. 4.3 Genomic Clustering
  4. 4.4 Target Mutation-based Mechanism
  5. 4.5 Predicting Drug Resistance in Other Organisms
  6. Acknowledgments
  7. References
Part 3 Fishing and Pharming
1. 5 Marine Bioprospecting
  1. 5.1 Introduction
  2. 5.2 International Treaties and Permit Issues
  3. 5.3 Techniques and Types of Collection
  4. 5.4 Screening Extracts vs. Fractions vs. Compounds
  5. 5.5 Chemical and Biological Screening Methods
  6. 5.6 Innovations on the Horizon
  7. 5.7 Conclusions
  8. Acknowledgments
  9. References
2. 6 Myxobacteria: Chemical Diversity and Screening Strategies
  1. 6.1 Introduction
  2. 6.2 Natural Products from Myxobacteria: Chemistry and Biological Activity, a Review of Publications Since 2009
  3. 6.3 Screening for New Scaffolds
  4. Acknowledgment
  5. References
3. 7 Fungal Endophytes of Grasses and Morning Glories, and Their Bioprotective Alkaloids
  1. 7.1 Introduction
  2. 7.2 Taxonomy of Clavicipitaceae and Host Grasses
  3. 7.3 Symbiosis Growth, Fruiting, and Pathogenesis
  4. 7.4 Endobiotic, Epibiotic, and Ectobiotic Growth
  5. 7.5 Phylogenetic Relationships
  6. 7.6 Ergot Alkaloids
  7. 7.7 Indole-Diterpenes
  8. 7.8 Peramine
  9. 7.9 Loline Alkaloids
  10. 7.10 Conclusions
  11. References
4. 8 Fungal-Actinomycete Interactions – Wakening of Silent Fungal Secondary Metabolism Gene Clusters via Interorganismic Interactions
  1. 8.1 Introduction
  2. 8.2 Microbial Regulatory Interactions
  3. 8.3 Interorganismal Interaction and Chromatin-Based Gene Regulation
  4. 8.4 Conclusions
  5. References
5. 9 Secondary Metabolites Produced by Plant Pathogens
  1. 9.1 Introduction
  2. 9.2 Bacterial Secondary Metabolites and Plant Disease
  3. 9.3 Fungal Secondary Metabolites as Host-Selective Toxins
  4. 9.4 A Secondary Metabolite as a Fungal Avirulence Factor
  5. 9.5 Non-Host-Selective Toxins and Plant Disease
  6. 9.6 Secondary Metabolite Gene Clusters and Horizontal Gene Transfer
  7. 9.7 Secondary Metabolite Toxins as Protection Against Predation
  8. 9.8 Conclusions and Future Directions
  9. Acknowledgments
  10. References

SECTION II FROM GENES TO MOLECULES

Part 1 Reading the Genome
1. 10 Analyzing Fungal Secondary Metabolite Genes and Gene Clusters
  1. 10.1 Introduction
  2. 10.2 Tools for Bioinformatics Analyses of Fungal SM Biosynthetic Pathways
  3. 10.3 From Genes to Chemical Structures
  4. 10.4 Prospects
  5. Acknowledgments
  6. References
Part 2 Biosynthesis and Heterologous Expression
1. 11 RiPPs: Ribosomally Synthesized and Posttranslationally Modified Peptides
  1. 11.1 Introduction
  2. 11.2 Lanthipeptides
  3. 11.3 Linear Azol(in)e-Containing Peptides (LAPs)
  4. 11.4 Thiopeptides
  5. 11.5 Cyanobactins
  6. 11.6 Lasso Peptides
  7. 11.7 Microviridins
  8. 11.8 Sactipeptides: Peptides Crosslinked by Cys to α-Carbon Linkages
  9. 11.9 Summary and Outlook
  10. References
2. 12 Polyketide Synthase: Sequence, Structure, and Function
  1. 12.1 Introduction
  2. 12.2 Similarity and Differences between PKS and FAS
  3. 12.3 Sequence–Structure–Function Relationship of PKS Domains
  4. 12.4 ACP and Sequestration Hypothesis of FAS and PKS
  5. 12.5 Conclusion and Future Directions
  6. References
3. 13 Manipulation of Fungal Natural Product Pathways
  1. 13.1 Introduction
  2. 13.2 Precursor-Directed Biosynthesis and Mutasynthesis
  3. 13.3 Gene Knockout and Silencing
  4. 13.4 Heterologous Expression
  5. 13.5 Yeast Expression
  6. 13.6 Gene Cluster Expression
  7. 13.7 Epigenetic Remodeling
  8. 13.8 Perspective
  9. References
4. 14 Production of Therapeutic Products
  1. 14.1 Introduction
  2. 14.2 The Production Host and the Influence on Process Development
  3. 14.3 Heterologous Natural Product Biosynthesis
  4. 14.4 Conclusions and Future Directions
  5. References
Part 3 Regulation: Waking Sleeping Pathways
1. 15 Waking Sleeping Pathways in Filamentous Fungi
  1. 15.1 Introduction
  2. 15.2 Discovery
  3. 15.3 One Strain Many Compounds
  4. 15.4 Interspecies Crosstalk
  5. 15.5 Molecular Manipulation
  6. 15.6 Epigenetic Manipulation
  7. 15.7 Heterologous Expression
  8. 15.8 Conclusions and Future Directions
  9. References

SECTION III EVOLVING ENZYMES, EVOLVING PATHWAYS: SYNTHETIC BIOLOGY

Part 1 Chemical Diversification
1. 16 The Oxidosqualene Cyclases: One Substrate, Diverse Products
  1. 16.1 Introduction
  2. 16.2 Animal and Fungal Oxidosqualene Cyclases
  3. 16.3 Plant Oxidosqualene Cyclases
  4. 16.4 Bacterial Squalene Cyclases
  5. 16.5 Conclusions and Future Directions
  6. References
2. 17 Harnessing Sugar Biosynthesis and Glycosylation to Redesign Natural Products and to Increase Structural Diversity
  1. 17.1 Introduction
  2. 17.2 Deoxysugar Biosynthesis
  3. 17.3 Deoxysugar Transfer
  4. 17.4 Deoxysugar Modification
  5. 17.5 In Vitro Glycorandomization
  6. 17.6 Conclusions and Prospects for the Future
  7. Acknowledgments
  8. References
Part 2 Evolving Pathways
1. 18 Evolutionary Mechanisms Involved in Development of Fungal Secondary Metabolite Gene Clusters
  1. 18.1 Introduction
  2. 18.2 Complex Evolution of Fungal Secondary Metabolism Gene Clusters: Two Case Studies
  3. 18.3 Conclusion
  4. References
Part 3 Synthetic Biology
1. 19 Synthetic Biology of Natural Products
  1. 19.1 Introduction
  2. 19.2 Computer-Aided Pathway Engineering
  3. 19.3 Rewriting the Genetic Code
  4. 19.4 Designer Cell Factories for Natural Products
  5. 19.5 Future Perspectives
  6. Acknowledgments
  7. References

SECTION IV SCREENING FOR BIOACTIVITY

20 Image-Based Screening Approaches to Natural Products Discovery
1. 20.1 Introduction
2. 20.2 Applications of Image-Based Screening to NP Discovery
3. 20.3 Future Perspective
4. References
21 Making Sense of Structures by Utilizing Mother Nature's Chemical Libraries as Leads to Potential Drugs
1. 21.1 Introduction
2. 21.2 Antidepressant Agents from Dyestuff Intermediates
3. 21.3 Benzopyrans, Unusual Antibacterial and Other Agents
4. 21.4 A Selection of Other Privileged Structural Classes
5. 21.5 Multiple Enzymatic Inhibitors from Relatively Simple Natural Product Secondary Metabolites
6. 21.6 The “Inside-Out” Approach
7. 21.7 Inhibitors of Protein–Protein Interactions
8. 21.8 Underprivileged Scaffolds
9. 21.9 Conclusion
10. References
22 Is There an Ideal Database for Natural Products Research?
1. 22.1 Introduction
2. 22.2 Requirements
3. 22.3 Reality
4. 22.4 Selection of a Database for Natural Products Research
5. 22.5 Future Directions
6. References

SECTION V TO APPLICATION

Case Studies
23 Daptomycin and A54145: Structure–Activity Relationship (SAR) Studies Enabled by Combinatorial Biosynthesis
1. 23.1 Introduction
2. 23.2 Daptomycin and A54145
3. 23.3 Combinatorial Biosynthesis Methodology
4. 23.4 Combinatorial Biosynthesis
5. 23.5 Genome Mining for Lipopeptide Biosynthetic Pathways
6. 23.6 Conclusions and Perspectives
7. References
24 Discovery and Development of NVB302, a Semisynthetic Antibiotic for Treatment of Clostridium difficile Infection
1. 24.1 Introduction
2. 24.2 Lantibiotic Biosynthesis
3. 24.3 Generation of Lantibiotic Libraries
4. 24.4 Chemical Semisynthesis
5. 24.5 Clostridium Difficile Infection
6. 24.6 NVB302 for C. difficile Infection
7. References
25 ILS-920: A Rapamycin Analog for Ischemic Stroke
1. 25.1 Introduction
2. 25.2 Design of Nonimmunosuppressive Rapamycin Analogs
3. 25.3 Pharmacokinetics and Brain Penetration of ILS-920
4. 25.4 ILS-920 Provides Long-Term Functional Recovery Following Permanent Middle Cerebral Artery Occlusion
5. 25.5 ILS-920 Promotes Survival of Multiple Brain Cell Types and Increases Immunohistochemical Markers of Regeneration Following MCAO
6. 25.6 Summary
7. Acknowledgments
8. References
26 BC265: A Nonquinone Ansamycin Hsp90 Inhibitor Developed Using Biosynthetic Medicinal Chemistry
1. 26.1 Introduction
2. 26.2 Next Generation Ansamycin Polyketide Hsp90 Inhibitors
3. 26.3 Rational Bioengineering of the Macbecin Biosynthetic Gene Cluster
4. 26.4 BC265 Is a Potent Inhibitor of Hsp90
5. 26.5 BC265 Exhibits an Improved Safety and Efficacy Profile
6. 26.6 Summary
7. Acknowledgments
8. References
27 Discovery and Development of Caspofungin (CANCIDAS): Concept to Clinic
1. 27.1 Introduction
2. 27.2 Discovery of Natural Product Lead
3. 27.3 Fermentation Development of Pneumocandin B₀: The Ultimate Lead for Making Caspofungin
4. 27.4 Chemical Optimization of Pneumocandin B₀ and Selection of the Preclinical Candidate
5. 27.5 Clinical Development of Caspofungin
6. References

Index

Discourse, Diversity, and Design