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Synthetic biology, genome mining, and combinatorial biosynthesis of NRPS-derived antibiotics: a perspective

  • Richard H. Baltz
Natural Products - Original Paper

Abstract

Combinatorial biosynthesis of novel secondary metabolites derived from nonribosomal peptide synthetases (NRPSs) has been in slow development for about a quarter of a century. Progress has been hampered by the complexity of the giant multimodular multienzymes. More recently, advances have been made on understanding the chemical and structural biology of these complex megaenzymes, and on learning the design rules for engineering functional hybrid enzymes. In this perspective, I address what has been learned about successful engineering of complex lipopeptides related to daptomycin, and discuss how synthetic biology and microbial genome mining can converge to broaden the scope and enhance the speed and robustness of combinatorial biosynthesis of NRPS-derived natural products for drug discovery.

Keywords

A54145 Actinomycetes CDA Combinatorial biosynthesis Daptomycin Genome mining Lipopeptide NRPS Streptomyces Synthetic biology 

Notes

Acknowledgements

I thank my many colleagues at Eli Lilly and Company and Cubist Pharmaceuticals who carried out exceptional industrial research on genetic manipulation and combinatorial biosynthesis of daptomycin and A54145 BGCs. Special thanks go to Margaret McHenney, Pat Solenberg, Patti Matsushima, and Tom Hosted at Lilly; and Vivian Miao, Kien Nguyen, Dylan Alexander, Steve Wrigley, Julia Penn, Steve Martin, Marie Coëffet-Le Gal, Sasha Doekel, Jian-Qiao Gu, Min Chu, and Paul Brian at Cubist. I also thank Hans von Döhren who suggested developing combinatorial biosynthesis between the daptomycin and A54145 NRPSs, and who was a collaborator on the initial project at Lilly.

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Copyright information

© Society for Industrial Microbiology and Biotechnology 2018
corrected publication March 2018

Authors and Affiliations

  1. 1.CognoGen Biotechnology ConsultingSarasotaUSA

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