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Transgenic pyrimethamine-resistant plasmodium falciparum reveals transmission-blocking potency of P218, a novel antifolate candidate drug
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Document Title
Transgenic pyrimethamine-resistant plasmodium falciparum reveals transmission-blocking potency of P218, a novel antifolate candidate drug
Author
Posayapisit N, Pengon J, Prommana P, Shoram M, Yuthavong Y, Uthaipibull C, Kamchonwongpaisan S, Jupatanakul N
Name from Authors Collection
Scopus Author ID
52364480000
Affiliations
National Science & Technology Development Agency - Thailand; National Center Genetic Engineering & Biotechnology (BIOTEC)
Type
Article
Source Title
INTERNATIONAL JOURNAL FOR PARASITOLOGY
ISSN
0020-7519
Year
2021
Volume
51
Issue
1
Open Access
Green Submitted
Publisher
ELSEVIER SCI LTD
DOI
10.1016/j.ijpara.2020.12.002
Format
Abstract
Antimalarial drugs capable of targeting multiple parasite stages, particularly the transmissible stages, can be valuable tools for advancing the malaria elimination agenda. Current antifolate drugs such as pyrimethamine can inhibit replicative parasite stages in both humans and mosquitoes, but antifolate resistance remains a challenge. The lack of reliable gametocyte-producing, antifolate-resistant Plasmodium falciparum laboratory strain hinders the study of new antifolate compounds that can overcome antifolate resistance including development stages in the mosquito. We used clustered regularly interspaced short palindromic repeats-Cas9 genome editing to develop a transgenic gametocyte-producing strain of P. falciparum with quadruple mutations (N51I, C59R, S108N, I164L) in the dihydrofolate reductase (dhfr) gene, using NF54 as a parental strain. The transgenic parasites exhibited pyrimethamine resistance while maintaining their gametocyte-producing activity. We then demonstrated that pyrimethamine could no longer inhibit male gametocyte exflagellation in the transgenic parasite. In contrast, P218, the novel antifolate, designed to overcome antifolate resistance, potently inhibited exflagellation. The exflagellation IC50 of P218 was five times lower than the asexual stage half maximal inhibitory concentration (IC50), suggesting a strong barrier for transmission of P218-resistant parasites. The transgenic gametocyte-producing, pyrimethamine-resistant parasite is a robust system for evaluating novel antifolate compounds against non-asexual stage development. (c) 2021 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.
Funding Sponsor
National Science and Technology Development Agency (NSTDA), Thailand [P-1850116]; BIOTEC Research Unit Director Initiative [P-1851424, P1551235]
License
CC BY-NC-ND
Rights
Australian Society for Parasitology
Publication Source
WOS