This unique, long-awaited volume is designed to address contemporary aspects of natural product chemistry and its influence on biological systems, not solely on human interactions. The subjects covered include discovery, isolation and characterization, biosynthesis, biosynthetic engineering, pharmaceutical, and other applications of these compounds.

Table of Contents

• Preface
• Editors
• Contributors
• Chapter 1 Microbial Genome Mining for Natural Product Drug Discovery - Richard H. Baltz
• 1.1 Introduction
• 1.1.1 Importance of Natural Products and the Issue of Rediscovery
• 1.1.2 Genome Mining Enhances Discovery and Circumvents Rediscovery
• 1.1.3 Scope of the Chapter
• 1.2 The New Central Dogma of Genome Mining
• 1.2.1 What Is Genome Mining and Why Is It Important?
• 1.2.2 What Are the Drivers for Successful Genome Mining?
• 1.2.2.1 Primary Drivers
• 1.2.2.2 Secondary Drivers
• 1.2.3 Strategies and Tactics for Genome Mining
• 1.2.3.1 Mining Individual Microbes
• 1.2.3.2 Mining Multiple Microbes
• 1.3 Future Directions
• 1.3.1 Expanded Sampling for Gifted Microbes
• 1.3.2 Expanded Efforts to Obtain Finished Genomes for Gifted Microbes
• 1.3.3 Leveraging Genomics for Combinatorial Biosynthesis
• References
• Chapter 2 Chemical Biology of Marine Cyanobacteria - Lena Keller, Tiago Leão, and William H. Gerwick
• 2.1 Introduction
• 2.2 Heterologous Expression of Cyanobacterial Natural Product Enzymes and Pathways
• 2.2.1 Expression of Biosynthetic Enzymes
• 2.2.1.1 Adenylation Domains
• 2.2.1.2 Barbamide Halogenase
• 2.2.1.3 Curacin A Biosynthetic Enzymes
• 2.2.1.4 Scytonemin Biosynthetic Enzymes
• 2.2.1.5 Lyngbyatoxin Biosynthetic Enzymes
• 2.2.1.6 Nostoc punctiforme Terpene Synthases and Cytochrome P450 (CYP)
• 2.2.1.7 Bartoloside Biosynthetic Enzymes
• 2.2.2 Heterologous Expression of Entire Biosynthetic Pathways
• 2.2.2.1 4-O-Demethylbarbamide
• 2.2.2.2 Lyngbyatoxin Production in Escherichia coli
• 2.2.2.3 Lyngbyatoxin Production in Anabaena sp. PCC7120
• 2.2.2.4 Expression of Ribosomally Encoded Peptides
• 2.3 Genetic Diversity of Secondary Metabolism in Cyanobacteria
• 2.3.1 Genetic Diversity and Distribution of Cyanobacterial Natural Product Pathways
• 2.3.1.1 Polyketides and Nonribosomal Peptides
• 2.3.1.2 Ribosomally Synthesized and Post-Translationally Modified Peptides
• 2.3.1.3 Indole-Alkaloids and Mycosporine-Like Amino Acids
• 2.3.2 Genome-Driven Drug Discovery in Cyanobacteria
• 2.4 Biotechnological Applications of Cyanobacterial Proteins
• 2.4.1 Phycobiliproteins
• 2.4.1.1 Phycobiliproteins as Fluorescent Agents
• 2.4.1.2 Phycobiliproteins as Natural Protein Dyes
• 2.4.1.3 Pharmaceutical Potential of Phycobiliproteins
• 2.4.2 Cyanophycin
• 2.4.3 Cyanovirin-N, an Anti-HIV Cyanobacterial Lectin
• 2.4.3.1 Mode of Action of Cyanovirin-N
• 2.4.4 Cyanobacteria as Green Cell Factories to Produce Biocatalytic Enzymes
• 2.4.4.1 Bioconversion of Hydrocortisone and Other Steroids
• 2.4.4.2 Production of Other Commercially Important Enzymes
• 2.4.4.3 Attempts to Increase the Production Efficacy in Cyanobacteria
• 2.5 Conclusion
• References
• Chapter 3 The Role of Combinatorial Biosynthesis in Natural Products Discovery - Jeffrey D. Rudolf, Ivana Crnovčić, and Ben Shen
• 3.1 Introduction
• 3.2 Nature, the Ultimate Combinatorial Biosynthetic Chemist
• 3.2.1 Platensimycin and Platencin
• 3.2.2 Tiancimycin, Uncialamycin, and Dynemycin
• 3.3 Knowledge-Based Combinatorial Biosynthesis
• 3.3.1 Deschloro-C-1027 and Desmethyl-C-1027
• 3.3.2 Bleomycin
• 3.4 Combinatorial Biosynthesis by Discovery
• 3.4.1 Strain Prioritization
• 3.4.2 Bioinformatics
• 3.5 Summary, Challenges, and Future Perspectives
• Acknowledgments
• References
• Chapter 4 Generation of New-to-Nature Natural Products through Synthesis and Biosynthesis: Blending Synthetic Biology with Synthetic Chemistry - Christopher S. Bailey, Emily R. Abraham, and Rebecca J.M. Goss
• 4.1 Introduction
• 4.1.1 Bioactive Natural Products and Their Roles in Nature and Medicine
• 4.1.2 Antibiotic Crisis and the Need for New Medicines
• 4.1.3 Natural Products and the Clinic: Toward New Antibiotics in the Battle against Resistance
• 4.2 Approaches to Generating Natural Product Analogues: Blending Synthetic Biology with Synthetic Chemistry
• 4.2.1 Synthetic Approaches (Chem)
• 4.2.2 Semisynthetic Approaches (Bio-Chem)
• 4.2.3 Precursor-Directed Biosynthesis (Chem-Bio)
• 4.2.4 Mutasynthesis (Bio-Chem-Bio)
• 4.2.5 Mutasynthesis Enabling Postbiosynthetic Modification (Bio-Chem-Bio-Chem)
• 4.2.6 Combinatorial Biosynthesis (Bio-Bio)
• 4.2.7 GenoChemetics: Gene Expression Enabling Synthetic Diversification (Bio-Bio-Chem)
• 4.2.8 Future Directions in Natural Product Analogue Generation
• Acknowledgments
• References
• Chapter 5 Terrestrial Microbial Natural Products Discovery Guided by Symbiotic Interactions and Revealed by Advanced Analytical Methods - Rita de Cássia Pessotti, Andrés Mauricio Caraballo-Rodríguez, Humberto Enrique Ortega-Domínguez, and Mônica Tallarico Pupo
• 5.1 Introduction
• 5.2 Chemical Ecology Knowledge for Selecting Microbial Strains as Sources of Bioactive Natural Products
• 5.2.1 Plant-Microorganisms System
• 5.2.1.1 Taxol: The Blockbuster Anticancer Drug
• 5.2.1.2 Chemical Biology History behind the Anticancer Drug Taxol
• 5.2.2 Insect-Associated Microbe Systems
• 5.2.2.1 Fungus-Growing Ants
• 5.2.2.2 Fungus-Growing Termites
• 5.2.2.3 Beetles
• 5.2.2.4 Wasps
• 5.2.2.5 Bees
• 5.3 Chemical Ecology Knowledge for Selecting Methodological Approach
• 5.3.1 Coculture Approach
• 5.3.1.1 Coculture of Endophytic Strains
• 5.3.1.2 Coculture of Pathogens
• 5.4 Analytical Techniques for Studying Microbial Natural Products
• 5.4.1 Classical Detectors
• 5.4.2 MS-Related Methods
• 5.4.3 Imaging-Related Techniques
• 5.4.4 Structural Elucidation
• 5.5 Final Remarks
• References
• Chapter 6 Natural Products from Endophytic Microbes: Historical Perspectives, Prospects, and Guidance - Gary Strobel
• 6.1 Introduction
• 6.2 Endophytic Microbes: Prospects
• 6.2.1 Endophyte Biology and the Plant Microbiome
• 6.2.2 Grass Endophytes: A Diversion
• 6.2.3 Taxol: A New Paradigm for Endophytes
• 6.2.4 Endophytes and Important Anticancer Compounds
• 6.3 Dealing with Endophytes
• 6.4 Examples from the Author's Laboratory of Bioactive Natural Products
• 6.4.1 Pestacin
• 6.4.2 Ambuic Acid
• 6.4.3 Torreyanic Acid
• 6.4.4 Colutellin A
• 6.4.5 Fungal Volatiles
• 6.5 Guidance and Perspective on the Future of Endophyte Biology and Natural Products Chemistry
• Acknowledgments
• References
• Chapter 7 Novel Insights in Plant–Endophyte Interactions - Souvik Kusari, Parijat Kusari, and Michael Spiteller
• 7.1 Introduction
• 7.2 Endophytes at the Center Stage of Nature's Biological Marketplace
• 7.3 Dynamics of Endophyte Interactions with Host Plants and Associated Organisms
• 7.3.1 Endophytic Fungal Interactions with Host Plants and Associated Endophytes
• 7.3.2 Endophytic Fungal Interactions with Endosymbiotic Bacteria
• 7.3.3 Endophytic Bacterial Interactions with Associated and Invading Bacteria
• 7.3.4 Endophytic Bacterial Communities
• 7.4 Outlook
• References
• Chapter 8 Microbial Coculture and OSMAC Approach as Strategies to Induce Cryptic Fungal Biogenetic Gene Clusters - Georgios Daletos, Weaam Ebrahim, Elena Ancheeva, Mona El-Neketi, Wenhan Lin, and Peter Proksch
• 8.1 Introduction
• 8.2 Production of Natural Products Following the OSMAC Approach
• 8.3 Induction of Natural Products through Cocultivation
• 8.4 Conclusion
• Acknowledgments
• References
• Chapter 9 Natural Products of the Rhizosphere and Its Microorganisms: Bioactivities and Implications of Occurrence - Maria C. F. de Oliveira, Jair Mafezoli, and A. A. Leslie Gunatilaka
• 9.1 General Introduction
• 9.2 Rhizosphere Microbial Diversity
• 9.2.1 Introduction
• 9.2.2 Bacterial Diversity
• 9.2.3 Fungal Diversity
• 9.3 Natural Products of the Rhizosphere
• 9.3.1 Introduction
• 9.3.2 Plant Metabolites
• 9.3.3 Bacterial Metabolites
• 9.3.4 Fungal Metabolites
• 9.4 Biological Activities of Rhizosphere Microbial Metabolites
• 9.4.1 Introduction
• 9.4.2 Metabolites of Agricultural Utility
• 9.4.3 Biological Activities Relevant to Drug Discovery
• 9.5 Implications of the Occurrence and Utilization of Natural Products of the Rhizosphere
• Acknowledgments
• References
• Chapter 10 Novel Metabolites from Extremophilic Microbes Isolated from Toxic Waste Sites - Andrea Stierle and Don Stierle
• 10.1 Introduction
• 10.2 Toxic Waste: The Next Frontier for the Discovery of Drug-Like Molecules
• 10.3 Evolution of an Extreme Ecosystem
• 10.4 Extreme Environments as a Source of Extremophilic Microorganisms
• 10.4.1 Extreme Environment
• 10.4.2 Different Categories of Extremophilic Microorganisms
• 10.5 Extremophiles from Naturally Occurring Extreme Environments as a Source of New Natural Products
• 10.5.1 Deep-Sea Vent Thermophiles
• 10.5.2 Secondary Metabolites from Deep-Sea Vent Thermophiles
• 10.6 Extremophiles from Natural Terrestrial Environments
• 10.7 Extremophiles from Anthropogenic Terrestrial Environments
• 10.7.1 Secondary Metabolites from a Coal Mine Acidophile
• 10.7.2 Secondary Metabolites from Tin Mine Alkaliphiles in Yunnan Province, China
• 10.7.3 Secondary Metabolites from an Underground Coal Fire Site
• 10.8 Bioprospecting in an EPA Superfund Site: The Search for Extremophiles
• 10.8.1 Search for Acidophilic Sulfate-Reducing Bacteria
• 10.8.2 Extremophilic Microbes of BPL
• 10.8.2.1 Isolation of the First Fungal Extremophiles
• 10.8.2.2 Initial Pilot Studies with BPL Fungi
• 10.8.3 Identification of Berkeley Pit Fungi
• 10.8.4 Challenges of Fungal Taxonomy
• 10.9 Search for Secondary Metabolites from Berkeley Pit Fungi
• 10.9.1 Prioritizing Microbes for Investigation
• 10.9.2 Selection of Appropriate Bioassays: The Path to MMP-3, Caspase-1, and Caspase-3
• 10.10 Correlations between BPL and Human Pathologies
• 10.10.1 Correlating Low pH and High Iron Concentration with Inflammation and Carcinogenesis
• 10.10.2 Enzymes Associated with Inflammation and Carcinogenesis: Caspase-1
• 10.10.3 Enzymes Associated with Inflammation and Carcinogenesis: MMP-3
• 10.10.4 Fungal Metacaspases, Apoptosis, and Mammalian Caspases
• 10.11 Mechanistic Pathways Associated with Inflammation and Carcinogenesis
• 10.11.1 Unresolved Inflammation
• 10.11.2 Caspase-1, the Inflammasome, and Inflammation
• 10.11.3 Correlating Inflammation and Metastasis
• 10.12 Correlating Metastasis with EMT and MMP-3
• 10.12.1 Prior Clinical Trials with MMP Inhibitors
• 10.12.2 Catalytic Mechanisms Involved in the Progression of EMT by MMP-3
• 10.12.3 EMT and the Noncatalytic HPEX Domain of MMP-3
• 10.12.3.1 MMP-3-HPEX Domain, HSP90b, and EMT
• 10.12.3.2 MMP-3-HPEX Domain, Wnt5b, and EMT
• 10.12.3.3 MMP-9-HPEX Domain and EMT
• 10.13 Connection between Inflammation and the EMT Molecular Pathway
• 10.14 Cerebral Ischemia, Caspase-3, and Apoptosis
• 10.14.1 Caspase-3 and the Intrinsic and Extrinsic Apoptotic Pathways
• 10.14.2 Animal Studies of Caspase-3 Upregulation Following Induced Strokes
• 10.15 Other Neuropathologies Associated with the Upregulation of Caspase-3
• 10.16 Results of Studies in the Stierle Research Laboratory
• 10.16.1 Small-Molecule Inhibitors That Target MMP-3 and Caspase-1
• 10.16.2 Results of Cell-Based Assays
• 10.16.2.1 Induced Inflammasome Assay and Caspase-1
• 10.16.2.2 Cell Invasion and Migration Assays and MMP-3
• 10.16.2.3 Oxygen-Glucose Deprivation Reperfusion Assay and Caspase-3
• 10.16.2.4 Overview of the MMP-3–ROS–Caspase-1 Cycle
• 10.17 Selected Secondary Metabolites of BPL Fungal Extremophiles
• 10.17.1 Enzyme Inhibitors and Inactive Analogs Produced by Berkeley Pit Microbes
• 10.17.2 X-Ray Crystallographic Studies of Inhibitor–Protein Interactions
• 10.18 MMP-3 and Caspase-1 Inhibitors
• 10.18.1 Berkelic Acid and Berkebisabolanes from a Green Alga–Associated Penicillium sp.
• 10.18.2 Meroterpenes from a Deep-Water Isolate of Penicillium rubrum
• 10.18.3 Azaphilones from Pleurostomophora sp
• 10.18.4 Phomopsolides from an Alga-Associated Penicillium sp
• 10.19 Use of SAR Information to Direct the Synthesis of More Potent Analogs
• 10.20 Conclusions and Future Directions
• References
• Chapter 11 Deep-Sea Hydrothermal Vent Organisms as Sources of Natural Products - Kerry L. McPhail, Eric H. Andrianasolo, David A. Gallegos, and Richard A. Lutz
• 11.1 Introduction
• 11.1.1 Distribution and Geology of Vents
• 11.1.2 Diversity and Biogeography of Vent Fauna
• 11.1.3 Phylogenetic Diversity of Vent Microorganisms
• 11.2 Small-Molecule Chemistry and Reported Biological Role or Activity
• 11.2.1 Primary-Type Metabolites
• 11.2.2 Secondary-Type Metabolites
• 11.3 Vent Microbial Metabolic Types
• 11.3.1 Influence of Vent Geochemistry on Metabolic Types of Microbes
• 11.3.2 Influence of Hydrostatic Pressure on Hydrothermal Vent Metabolisms
• 11.3.3 Microbial Symbionts of Deep-Sea Vent Organisms
• 11.4 Cultivation of Deep-Sea Vent Organisms
• 11.4.1 New Strains Isolated in Culture
• 11.4.2 New Technologies for Culturing
• 11.5 Development of Other Bioproducts
• 11.6 Concluding Remarks
• Acknowledgments
• References
• Chapter 12 Cone Snail Venom Peptides and Future Biomedical Applications of Natural Products - Baldomero M. Olivera, Helena Safavi-Hemami, Shrinivasan Raghuraman, and Russell W. Teichert
• 12.1 Introduction
• 12.1.1 General Biological Framework for Natural Products
• 12.1.2 Conus Venom Peptides as Natural Products
• 12.1.3 Case Study of Chemical Interactions: The Skunk
• 12.1.4 Chemical Neuroethology Defined: A Division of Systems Biology
• 12.1.5 Drug Development: Why Natural Products Have Largely Been Abandoned (and Why They Should Not Be)
• 12.2 Conus geographus, Venom Peptides, and Behavior
• 12.2.1 Correlating Behavior and Chemistry
• 12.2.2 Motor Cabal of Conus geographus
• 12.2.3 Nirvana Cabal
• 12.3 Taser-and-Tether Strategy of Fish-Hunting Cone Snails
• 12.3.1 Overview
• 12.3.2 Lightning-Strike Cabal
• 12.3.3 Motor Cabal of Taser-and-Tether Cone Snail Species
• 12.4 Major Characterized Molecular Targets of Conus Venom Peptides
• 12.4.1 Overview
• 12.4.2 Conopeptides Targeted to Voltage-Gated Na Channels
• 12.4.2.1 Pore Blockers of Voltage-Gated Na Channels: μ-Conotoxins
• 12.4.2.2 μO-Conotoxins: Conus Peptides That Inhibit Activation
• 12.4.2.3 Conopeptides Targeted to Voltage-Gated Na Channels That Increase Excitability
• 12.4.3 Conopeptides Targeted to Voltage-Gated K Channels
• 12.4.4 Conopeptides Targeted to Voltage-Gated Ca Channels
• 12.4.5 Conopeptides Targeted to Nicotinic Acetylcholine Receptors
• 12.4.6 Other Families of Conus Venom Peptides Targeted to Nicotinic Acetylcholine Receptors
• 12.4.7 Conopeptides Targeted to Glutamate Receptors
• 12.4.8 Other Conopeptide Targets
• 12.5 Biomedically Significant Conus Venom Peptides: Therapeutic, Diagnostic, and Basic Research Applications
• 12.5.1 ω-Conotoxins, ω-Conotoxin GVIA, and ω-Conotoxin MVIIA
• 12.5.2 α-Conotoxins Vc1.1 and Rg1A
• 12.5.3 Contulakin-G
• 12.5.4 Conantokins
• 12.5.5 Con-Insulin
• 12.5.6 χ-Conotoxins
• 12.6 Conus Venom Peptides: Unusual Gene Products
• 12.6.1 Conotoxin Classification and Genetic Diversity
• 12.6.2 Diversity of Post-Translational Modifications Observed in Conus
• 12.6.3 Conus Venom Insulins: Insights into How Natural Product Evolution Refines Structure and Function
• 12.7 Perspectives
• Acknowledgments
• References
• 12A Appendix: List of Conotoxins Grouped by Molecular Targets
• Chapter 13 Naturally Occurring Disulfide-Rich Cyclic Peptides from Plants and Animals: Synthesis and Biosynthesis - Simon J. de Veer and David J. Craik
• 13.1 Introduction
• 13.1.1 Sunflower Trypsin Inhibitor-1 and Other PawS-Derived Peptides
• 13.1.2 Two-Disulfide Cyclic Conotoxins
• 13.1.3 Theta-Defensins
• 13.1.4 Cyclotides
• 13.1.5 Cyclic Three-Disulfide Conotoxins
• 13.1.6 Cyclic Four-Disulfide Chlorotoxins
• 13.2 Approaches to the Synthesis of Disulfide-Rich Cyclic Peptides
• 13.2.1 Strategies for Producing Cyclic Peptides: Synthetic Chemistry
• 13.2.1.1 Cyclization Using Chemical Coupling Reagents
• 13.2.1.2 Native Chemical Ligation
• 13.2.1.3 Chemoenzymatic Cyclization
• 13.2.2 Strategies for Producing Cyclic Peptides: Biosynthesis
• 13.2.2.1 Expressed Protein Ligation
• 13.2.2.2 Protein Trans-Splicing
• 13.2.2.3 In Planta Cyclization
• 13.3 Cyclic Peptides as Engineering Templates for Designing New Chemical Tools
• 13.3.1 Engineered Protease Inhibitors
• 13.3.2 Ultrastable Scaffolds for Displaying Bioactive Peptide Sequences
• 13.3.3 Cyclic Peptide Libraries for Developing New Chemical Tools
• 13.4 Overview and Perspectives
• Acknowledgments
• References
• Chapter 14 Synthesis and Target Identification of Natural Product–Inspired Compound Collections - Luca Laraia and Herbert Waldmann
• 14.1 Introduction
• 14.1.1 Chemical Space and Natural Products
• 14.1.2 Structural Classification of Natural Products (SCONP)
• 14.1.3 Protein Structure Similarity Clustering
• 14.1.4 Biology-Oriented Synthesis
• 14.2 Strategies for the Synthesis of Natural Product-Inspired Collections
• 14.3 Target Identification
• 14.3.1 Educated Guesses
• 14.3.2 Image Analysis
• 14.3.3 Structural Similarities and the Computational Approach
• 14.3.4 Proteomic Approach
• 14.4 Summary
• References
• Chapter 15 On the Chemistry and Biology of the Marine Macrolides Zampanolide and Dactylolide - Karl-Heinz Altmann, Simon Glauser, and Tobias Brütsch
• 15.1 Introduction
• 15.2 Zampanolide and Dactylolide: Isolation and Structure
• 15.3 Biological Activity of Zampanolide and Dactylolide
• 15.4 Total Synthesis of Zampanolide and Dactylolide
• 15.4.1 Previous Syntheses
• 15.4.2 Total Synthesis of (-)-Zampanolide and (-)-Dactylolide by Zurwerra et al.
• 15.5 Synthesis of Analogs
• 15.6 Structure–Activity Relationships
• 15.7 Mode of Action and Binding to Tubulin
• 15.8 Conclusions
• References