Malaria infects 300–500 million people and causes 1-2 million deaths each year, primarily children in Africa and Asia. One of the principal obstacles to addressing this global health threat is a lack of effective, affordable drugs. The chloroquine-based drugs that were used widely in the past have lost effectiveness because the Plasmodium parasite which causes malaria has become resistant to them.  The faster-acting, more effective artemisinin-based drugs — as currently produced from plant sources — are too expensive for large-scale use in the countries where they are needed most.  The Keasling laboratory engineered both Escherichia coli and Saccharomyces cerevisiae to produce a precursor to artemisinin, artemisinic acid, which can be readily converted into artemisinin.  Microbial production of artemisinic acid will eventually reduce the cost of artemisinin-based combination therapies significantly below their current price and stabilize the supply of artemisinin while controlling access.  Our partner in this work was Amyris Biotechnologies, a company founded to develop and optimize this technology.  Sanofi licensed the technology and scaled it.  They began shipping artemisinin combination therapies containing artemisinin produced using this microbial production process in August, 2014.  As of May 2015, they had shipped 15 million treatments to Africa.

Artemisinin
                      Artemisinin
FUNDING

National Science Foundation

Bill & Melinda Gates Foundation

LINKS

Berkeley News story on launch of artemisinin

Sanofi-Aventis press release (pdf)

REPRESENTATIVE PUBLICATIONS
  • V. J. J. Martin, D. J. Pitera, S. T. Withers, J. D. Newman, and J. D. Keasling. 2003. “Engineering the mevalonate pathway in Escherichia coli for production of terpenoids.” Nat. Biotechnol. 21:796-802.
  • D-K. Ro, E. M. Paradise, M. Ouellet, K. J. Fisher, K. L. Newman, J. M. Ndungu, K. A. Ho, R. A. Eachus, R. S. Ham, J. Kirby, M. C. Y. Chang, S. T. Withers, Y. Shiba, R. Sarpong, and J. D. Keasling. 2006. “Production of the antimalarial drug precursor artemisinic acid in engineered yeast.” Nature 440:940-943.
  • J. D. Newman, J. Marshal, M. Chang, F. Nowroozi, E. Paradise, D. Pitera, K. L. Newman, and J. D. Keasling. 2006. “High-level production of amorpha-4,11-diene in a two-phase partitioning bioreactor of metabolically engineering Escherichia coli.” Biotechnol. Bioeng. 95:684-691.
  • B.F. Pfleger, D. J. Pitera, J. D. Newman, V. J. J. Martin, and J. D. Keasling. 2007. “Microbial sensors for small molecules: development of a mevalonate biosensor.” Metab. Eng. 9:30-38.
  • Y. Shiba, E. M. Paradise, J. Kirby, D.-K. Ro, and J. D. Keasling. 2007. “Engineering of the pyruvate dehydrogenase bypass in Saccharomyces cerevisiae for high-level production of isoprenoids.” Metab. Eng. 9:160-168.
  • D. J. Pitera, C. J. Paddon, J. D. Newman, and J. D. Keasling. 2007. “Balancing a heterologous mevalonate pathway for improved isoprenoid production in Escherichia coli.” Metab. Eng. 9:193-207.
  • V. Hale, J. D. Keasling, N. Renninger, and T. T. Diagana. 2007. “Microbially derived artemisinin: a biotechnology solution to the global problem of access to affordable anti-malarial drugs.” Am. J. Trop. Med. Hyg. 77:198-202.
  • L. Kizer, D. J. Pitera, B. Pfleger, and J. D. Keasling. 2008. “Functional genomics for pathway optimization: application to isoprenoid production.” Appl. Environ. Microbiol. 74:3229-3241.
  • E. M. Paradise, J. Kirby, R. Chan, and J. D. Keasling. 2008. “Redirection of flux through the FPP branch-point in Saccharomyces cerevisiae by downregulating squalene synthase.” Biotechnol. Bioeng. 100:371-378.
  • J. Kirby and J. D. Keasling. 2008. “Metabolic engineering of microorganisms for isoprenoid production.” Nat. Prod. Rep. 25:656-661.
  • D. Lubertozzi and J. D. Keasling. 2008. “Expression of a synthetic Artemisia annua amorphadiene synthase in Aspergillus nidulans yields altered product distribution.” J. Ind. Microbiol. Biotechnol. 35:1191-1198.
  • D.-K. Ro, M. Ouellet, E. M. Paradise, H. Burd, D. Eng, C. J. Paddon, J. D. Newman, and J. D. Keasling. 2008. “Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of antimalarial drug precursor, artemisinic acid.” BMC Biotechnol. 8:83 (doi:10.1186/1472-6750-8-83).
  • J. R. Anthony, L. C. Anthony, F. Nowroozi, G. Kwon, J. D. Newman, and J. D. Keasling. 2009. “Optimization of the mevalonate-based isoprenoid biosynthetic pathway in E. coli for production of the anti-malarial drug precursor amorpha-4,11-diene.” Met. Eng. 11:13-19.
  • H. Tsuruta, C. J. Paddon, D. Eng, J. R. Lenihan, T. Horning, L. C. Anthony, R. Regentin, J. D. Keasling, N. S. Renninger, and J. D. Newman. 2009. “High-level production of amorpha-4,11-diene, a precursor of the antimalarial agent artemisinin, in Escherichia coli.” PLOS One 4:e4489 doi:10.1371.
  • J. Dietrich, Y. Yoshikuni, K. Fisher, F. Woolard, D. Ockey, D. McPhee, N. Renninger, M. Chang, D. Baker, and J. D. Keasling. 2009. “A novel semi-biosynthetic route for artemisinin production using engineered substrate-promiscuous P450BM3.” ACS Chem. Biol. 4:261-267.
  • J. E. Dueber, G. C. Wu, G. R. Malmirchegini, T. S. Moon, C. J. Petzold, A. V. Ullal, K. J. Prather, and J. D. Keasling. 2009. “Synthetic protein scaffolds provide modular control over metabolic flux.” Nat. Biotechnol. 27:753-759.
  • J. D. Keasling. 2010. “Manufacturing molecules through metabolic engineering.” Science 330:1355-1358.
  • S. M. Ma, D. E. Garcia, A. M. Redding-Johanson, G. D. Friedland, R. Chan, T. S. Batth, J. R. Haliburton, D. Chivian, J. D. Keasling, C. J. Petzold, T. S. Lee, S. R. Chhabra. 2011. “Optimization of a heterologous mevalonate pathway through use of variant HMG-CoA reductases.” Met. Eng. 13:588-597.
  • P. J. Westfall, D. J. Pitera, J. R. Lenihan, D. Eng, F. Woolard, R. Regentin, T. Horning, Hiroko Tsuruta, D. Melis, A. Owens, S. Fickes, D. Diola, J. D. Keasling, M. D. Leavell, D. McPhee, N. S. Renninger, J. D. Newman, C. J. Paddon. 2012. “Production of Amorpha-4,11-diene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin.” Proc. Natl. Acad. Sci. USA 109:E111-E118.
  • J. D. Keasling. 2012. “Engineering biology for drugs and fuels.” Proc. Amer. Philosoph. Soc. 156:283-294.
  • C. J. Paddon, P. J. Westfall, D. J. Pitera, K. Benjamin, K. Fisher, D. McPhee, M. D. Leavell, A. Tai, A. Main, D. Eng, D. R. Polichuk, K. H. Teoh, D. W. Reed, T. Treynor, J. Lenihan, M. Fleck, S. Bajad, G. Dang, D. Diola, G. Dorin, K. W. Ellens, S. Fickes, J. Galazzo, S. P. Gaucher, T. Geistlinger, R. Henry, M. Hepp, T. Horning, T. Iqbal, H. Jiang, L. Kizer, B. Lieu, D. Melis, N. Moss, R. Regentin, S. Secrest, H. Tsuruta, R. Vazquez, L. F. Westblade, L. Xu, M. Yu, Y. Zhang, L. Zhao, J. Lievense, P. S. Covello, J. D. Keasling, K. K. Reiling, N. S. Renninger & J. D. Newman. 2013. “High-level semi-synthetic production of the potent antimalarial artemisinin.” Nature 496:528-532.
  • R. H. Dahl, F. Zhang, J. Alonso-Gutierrez, E. Baidoo, T. S. Batth, A. M. Redding-Johanson, C. J. Petzold, A. Mukhopadhyay, T. Soon Lee, P. D. Adams, and J. D. Keasling. 2013. “Engineering dynamic pathway regulation using stress-response promoters.” Nat. Biotechnol. 31(11):1039-1046. doi: 10.1038/nbt.2689.
  • J. D. Keasling and J. C. Venter. 2013. “Applications of synthetic biology to enhance life.” The Bridge 43:47-58.
  • H. M. Woo, G. W. Murray, T. S. Batth, N. Prasad, P. D. Adams, J. D. Keasling, C. J. Petzold, and T. S. Lee. 2013. “Application of targeted proteomics and biological parts assembly in E. coli to optimize the biosynthesis of an anti-malarial drug precursor, amorpha-4,11-diene.” Chem. Eng. Sci. 103:21-28.
  • F. F. Nowroozi, E. E. Baidoo, S. Ermakov, A. M. Redding-Johanson, T. S. Batth, C. J. Petzold, and J. D. Keasling. 2013. “Metabolic pathway optimization using ribosome binding site variants and combinatorial gene assembly.” Appl. Microbiol. Biotechnol. 98:1567-1581.
  • C. J. Paddon and J. D. Keasling. 2014. “Semi-synthetic artemisinin: a model for the use of synthetic biology in pharmaceutical development.” Nat. Rev. Microbiol. 12:355-367.