Abstract
Malaria is a real and constant danger to nearly half of the world’s population of 7.4 billion people. In 2015, 212 million cases were reported along with 429,000 estimated deaths. The World Health Organization recommends artemisinin-based combinatorial therapies, and the artemisinin for this purpose is mainly isolated from the plant Artemisia annua. However, the plant supply of artemisinin is irregular, leading to fluctuation in prices. Here, we report the development of a simple, sustainable, and scalable production platform of artemisinin. The five genes involved in artemisinin biosynthesis were engineered into the moss Physcomitrella patens via direct in vivo assembly of multiple DNA fragments. In vivo biosynthesis of artemisinin was obtained without further modifications. A high initial production of 0.21 mg/g dry weight artemisinin was observed after only 3 days of cultivation. Our study shows that P. patens can be a sustainable and efficient production platform of artemisinin that without further modifications allow for industrial-scale production. A stable supply of artemisinin will lower the price of artemisinin-based treatments, hence become more affordable to the lower income communities most affected by malaria; an important step toward containment of this deadly disease threatening millions every year.
Highlights
Physcomitrella patens is a non-vascular plant that has been well established as a model organism to be used in basic research and in applied biotechnology (Simonsen et al, 2009; Buttner-Mainik et al, 2011; Ikram et al, 2015; Reski et al, 2015)
A novel transformation technology involving in vivo assembly of multiple DNA fragments in P. patens has been established, further increasing the potential as a photosynthetic chassis for synthetic biology (King et al, 2016)
There are no reports on the stable heterologous biosynthesis of artemisinin in photosynthetic organisms that can be grown in bioreactors
Summary
Physcomitrella patens is a non-vascular plant that has been well established as a model organism to be used in basic research and in applied biotechnology (Simonsen et al, 2009; Buttner-Mainik et al, 2011; Ikram et al, 2015; Reski et al, 2015). Several efforts have been made to obtain artemisinin from a stable source, such as yeast (Ro et al, 2006), where a production of artemisinic acid followed by a three-step chemical synthesis to artemisinin was established (Paddon and Keasling, 2014). It was previously shown that artemisinin could be mass-produced by cultivation of A. annua or semi-synthetically in microorganisms producing artemisinic acid (Paddon and Keasling, 2014). Besides these efforts, extensive bioengineering of modified Nicotiana plants (Malhotra et al, 2016; Wang et al, 2016) has provided limited production of artemisinin. There are no reports on the stable heterologous biosynthesis of artemisinin in photosynthetic organisms that can be grown in bioreactors
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