CHAPTER SIX Production of Specialized Metabolites by Streptomyces coelicolor A3(2) Geertje van Keulen 1 , Paul J. Dyson Institute of Life Science, College of Medicine, Swansea University, Swansea, Wales, United Kingdom 1 Corresponding author: e-mail address: g.van.keulen@swansea.ac.uk Contents 1. Introduction 218 2. Morphology and Life Cycle 219 3. Genome Architecture 220 4. Specialized Metabolites of S. coelicolor 221 4.1 Classes of natural products and biosynthetic gene clusters 223 4.2 Mechanisms for transport of specialized metabolites over the cell membrane 240 5. Regulation of Specialized Metabolism 242 5.1 Growth and development 244 5.2 Nutrition 246 5.3 Cross talk 247 5.4 Facilitating export 248 5.5 CPK: Activating a cryptic gene cluster 248 6. Modulation of Antibiotic Titers 249 6.1 Manipulation of RNA polymerase function 250 6.2 Ribosome engineering 251 6.3 Metals 251 6.4 S-Adenosyl methionine 252 6.5 Nucleoid structural changes 252 6.6 Exploiting chemical interactions 253 6.7 Site-specific recombineering for targeted amplification of gene clusters 254 7. Exploiting S. coelicolor as a Generic Host for Antibiotic Production 254 8. Future Perspectives and Concluding Remarks 255 Acknowledgments 256 References 256 Abstract The actinomycetes are well-known bioactive natural product producers, comprising the Streptomycetes, the richest drug-prolific family in all kingdoms, producing therapeutic compounds for the areas of infection, cancer, circulation, and immunity. Completion Advances in Applied Microbiology, Volume 89 # 2014 Elsevier Inc. ISSN 0065-2164 All rights reserved. http://dx.doi.org/10.1016/B978-0-12-800259-9.00006-8 217