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-Aventis has licensed the technology and is currently optimizing and scaling the process.
- J. E. Dueber, G. C. W, 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. 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.
- 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. 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.
- 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).
- 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.
- 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.
- D. Luberbozzi 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.
- 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.
- M. C. Y. Chang, R. A. Eachus, W. Trieu, D.-K. Ro, and J. D. Keasling. 2007. “Engineering Escherichia coli for production of functionalized terpenoids using plant P450s.” Nature Chem. Biol. 3:274-277.
- 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.
- 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.
- 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, C. D. Smolke, and J. D. Keasling. 2006. “Combinatorial engineering of intergenic regions in operons tunes expression of multiple genes.” Nat. Biotechnol. 24:1027-1032.
- 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.
- 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.