Czechowski, T, Rinaldi, M, Famodimu, M, Van Veelen, M, Larson, T, Winzer, T, Rathbone, D, Harvey, D, Horrocks, P ORCID: https://orcid.org/0000-0003-3981-0732 and Graham, I (2019) Flavonoid versus artemisinin anti-malarial activity in Artemisia annua whole-leaf extracts. Frontiers in Plant Science, 10.

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Abstract

Artemisinin, a sesquiterpene lactone produced by Artemisia annua glandular secretory trichomes, is the active ingredient in the most effective treatment for uncomplicated malaria caused by Plasmodium falciparum parasites. Other metabolites in A. annua or related species, particularly flavonoids, have been proposed to either act as antimalarials on their own or act synergistically with artemisinin to enhance antimalarial activity. We identified a mutation that disrupts the CHALCONE ISOMERASE 1 (CHI1) enzyme that is responsible for the second committed step of flavonoid biosynthesis. Detailed metabolite profiling revealed that chi1-1 lacks all major flavonoids but produces wild-type artemisinin levels, making this mutant a useful tool to test the antiplasmodial effects of flavonoids. We used whole-leaf extracts from chi1-1 and mutant lines impaired in artemisinin production in bioactivity in vitro assays against intraerythrocytic P. falciparum Dd2. We found that chi1-1 extracts did not differ from wild-type extracts in antiplasmodial efficacy nor initial rate of cytocidal action. Furthermore, extracts from the A. annua cyp71av1-1 mutant and RNAi lines impaired in amorpha-4,11-diene synthase gene expression, which are both severely compromised in artemisinin biosynthesis but unaffected in flavonoid metabolism, showed very low or no antiplasmodial activity. These results demonstrate that in vitro bioactivity against P. falciparum of flavonoids is negligible when compared to that of artemisinin.

Item Type: Article
Additional Information: This is the final published version of the article (version of record). It first appeared online via Frontiers Media at http://doi.org/10.3389/fpls.2019.00984 - please refer to any applicable terms of use of the publisher.
Uncontrolled Keywords: Malaria, Artemisia annua, Artemisinin, Flavonoids, Plasmodium falciparum, Chalcone isomerase
Subjects: Q Science > Q Science (General)
Q Science > QH Natural history
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Depositing User: Symplectic
Date Deposited: 15 Jul 2019 07:56
Last Modified: 19 Aug 2019 08:40
URI: http://eprints.keele.ac.uk/id/eprint/6574

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