NATURAL PRODUCTS. DISCOURSE, DIVERSITY, AND DESIGN

SECTION I NATURAL PRODUCTS IN THE NATURAL WORLD 1
Part 1 Role and Reason 3
1 The Role of Phytochemicals in Relationships of Plants with Other Organisms 5
2 Designer Microbial Ecosystems – Toward Biosynthesis with Engineered Microbial Consortia 23
3 Marine Natural Products – Chemical Defense/Chemical Communication in Sponges and Corals 39

Part 2 Self-Protection – Avoiding Autotoxicity 67
4 How Plants Avoid the Toxicity of Self-Produced Defense Bioactive Compounds 69

Part 3 Fishing and Pharming 83
5 Marine Bioprospecting 85
6 Myxobacteria: Chemical Diversity and Screening Strategies 103
7 Fungal Endophytes of Grasses and Morning Glories, and their Bioprotective Alkaloids 125
8 Fungal-Actinomycete Interactions –Wakening of Silent Fungal Secondary Metabolism Gene Clusters via Interorganismic Interactions 147
9 Secondary Metabolites Produced by Plant Pathogens 159

SECTION II FROM GENES TO MOLECULES 171
Part 1 Reading the Genome 173
10 Analyzing Fungal Secondary Metabolite Genes and Gene Clusters 175

Part 2 Biosynthesis and Heterologous Expression 195
11 RiPPs: Ribosomally Synthesized and Posttranslationally Modified Peptides 197
12 Polyketide Synthase: Sequence, Structure, and Function 219
13 Manipulation of Fungal Natural Product Pathways 245
14 Production of Therapeutic Products 261

Part 3 Regulation: Waking Sleeping Pathways 277
15 Waking Sleeping Pathways in Filamentous Fungi 279

SECTION III EVOLVING ENZYMES, EVOLVING PATHWAYS: SYNTHETIC BIOLOGY 293
Part 1 Chemical Diversification 295
16 The Oxidosqualene Cyclases: One Substrate, Diverse Products 297
17 Harnessing Sugar Biosynthesis and Glycosylation to Redesign Natural Products and to Increase Structural Diversity 317

Part 2 Evolving Pathways 341
18 Evolutionary Mechanisms Involved in Development of Fungal Secondary Metabolite Gene Clusters 343

Part 3 Synthetic Biology 357
19 Synthetic Biology of Natural Products 359

SECTION IV SCREENING FOR BIOACTIVITY 371
20 Image-Based Screening Approaches to Natural Products Discovery 373
21 Making Sense of Structures by Utilizing Mother Nature’s Chemical Libraries as Leads to Potential Drugs 397
22 Is There an Ideal Database for Natural Products Research? 413

SECTION V TO APPLICATION 433
Case Studies 435
23 Daptomycin and A54145: Structure–Activity Relationship (SAR) Studies Enabled by Combinatorial Biosynthesis 437
24 Discovery and Development of NVB302, a Semisynthetic Antibiotic for Treatment of Clostridium difficile Infection 455
25 ILS-920: A Rapamycin Analog for Ischemic Stroke 469
26 BC265: A Nonquinone Ansamycin Hsp90 Inhibitor Developed Using Biosynthetic Medicinal Chemistry 483
27 Discovery and Development of Caspofungin (CANCIDAS): Concept to Clinic 497

Index 523

Natural Products: Discourse, Diversity and Design provides an informative and accessible overview of discoveries in the area of natural products in the genomic era, bringing together advances across the kingdoms. As genomics data makes it increasingly clear that the genomes of microbes and plants contain far more genes for natural product synthesis than had been predicted from the numbers of previously identified metabolites, the potential of these organisms to synthesize diverse natural products is likely to be far greater than previously envisaged. Natural Products addresses not only the philosophical questions of the natural role of these metabolites, but also the evolution of single and multiple pathways, and how these pathways and products may be harnessed to aid discovery of new bioactives and modes of action.

Authors
• Anne Osbourn is Professor at the University of East Anglia, UK, and Director of the Norwich Research Park Industrial Biotechnology and Bioenergy Alliance, and is based at the John Innes Centre.
• Rebecca J. Goss is Reader in Organic/Biomolecular Chemistry at the School of Chemistry and also at the Biomedical Sciences Research Complex at the University of St Andrews, UK.
• Guy T. Carter has over 30 years of experience working in Pharmaceutical R&D, primarily in the discovery and development of microbial products. He is currently CEO of Carter–Bernan Consulting and Chief Scientific Officer at Biosortia Pharmaceuticals, USA.