Abstract
Commercial Artemisia annua crops are the sole source of artemisinin (ART) worldwide. Data on seasonal accumulation and peak of sesquiterpenes, especially ART in commercial A. annua, is lacking while current breeding programs focus only on ART and plant biomass, but ignores dihydroartemisinic acid (DHAA) and artemisinic acid (AA). Despite past breeding successes, plants richer in ART are needed to decrease prices of artemisinin-combination therapy (ACT). Our results show that sesquiterpene concentrations vary greatly along the growing season and that sesquiterpene profiles differ widely among chemotypes. Field studies with elite Brazilian, Chinese, and Swiss germplasms established that ART peaked in vegetative plants from late August to early September, suggesting that ART is related to the photoperiod, not flowering. DHAA peaks with ART in Chinese and Swiss plants, but decreases, as ART increases, in Brazilian plants, while AA remained stable through the season in these genotypes. Chinese plants peaked at 0.9% ART, 1.6% DHAA; Brazilian plants at 0.9% ART, with less than 0.4% DHAA; Swiss plants at 0.8% ART and 1% DHAA. At single-date harvests, seeded Swiss plants produced 0.55–1.2% ART, with plants being higher in DHAA than ART; Brazilian plants produced 0.33–1.5% ART, with most having higher ART than DHAA. Elite germplasms produced from 0.02–0.43% AA, except Sandeman-UK (0.4–1.1% AA). Our data suggest that different chemotypes, high in ART and DHAA, have complementary pathways, while competing with AA. Crossing plants high in ART and DHAA may generate hybrids with higher ART than currently available in commercial germplasms. Selecting for high ART and DHAA (and low AA) can be a valuable approach for future selection and breeding to produce plants more efficient in transforming DHAA into ART in planta and during post-harvest. This novel approach could change the breeding focus of A. annua and other pharmaceutical species that produce more than one desired metabolite in the same pathway. Obtaining natural variants with high ART content will empower countries and farmers who select, improve, and cultivate A. annua as a commercial pharmaceutical crop. This selection approach could enable ART to be produced locally where it is most needed to fight malaria and other parasitic neglected diseases.
Highlights
Active pharmaceutical ingredients (APIs) based on artemisinin (ART), such as artemether and artesunate, are key components of the most effective antimalarial drugs
Rather than pursuing ART production in heterologous systems, more viable approaches to increase plant-based ART supply should focus on: (1) breeding plants that are higher in ART than the currently reported average of approximately 1.5% ART, (2) producing cultivars that are less variable in plant-toplant ART concentrations, (3) producing cultivars that are higher in DHAA and able to convert DHAA into ART more efficiently, (4) improving ART commercial extraction to over 70% efficiency, and (5) recycling DHAA from ART commercial waste to produce more ART
The peak for DHAA concentration coincided with ART in the Chinese and Swiss plants, whereas DHAA was lower than ART during most of the season in Brazilian plants
Summary
Active pharmaceutical ingredients (APIs) based on artemisinin (ART), such as artemether and artesunate, are key components of the most effective antimalarial drugs. Other plants and microorganisms have been engineered with ART-pathway genes, tobacco was only able to produce artemisinic acid (AA) at 0.12% of leaf dry weight (DW) (Fuentes et al, 2016), and ART at less than 0.0007% of leaf DW (Farhi et al, 2011); transgenic moss produced ART at 0.021% of leaf DW (Khairul Ikram et al, 2017). These yields are 47 (moss) to 1,400 times (tobacco) less than an A. annua plant that produces 1% ART. Rather than pursuing ART production in heterologous systems, more viable approaches to increase plant-based ART supply should focus on: (1) breeding plants that are higher in ART than the currently reported average of approximately 1.5% ART, (2) producing cultivars that are less variable in plant-toplant ART concentrations, (3) producing cultivars that are higher in DHAA and able to convert DHAA into ART more efficiently, (4) improving ART commercial extraction to over 70% efficiency, and (5) recycling DHAA from ART commercial waste to produce more ART
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