Transgenic pyrimethamine-resistant plasmodium falciparum reveals transmission-blocking potency of P218, a novel antifolate candidate drug
Autor: | Molnipha Shoram, Sumalee Kamchonwongpaisan, Parichat Prommana, Yongyuth Yuthavong, Navaporn Posayapisit, Jutharat Pengon, Chairat Uthaipibull, Natapong Jupatanakul |
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Rok vydání: | 2021 |
Předmět: |
Male
0301 basic medicine Transgene Plasmodium falciparum 030231 tropical medicine Drug Resistance Drug resistance Antimalarials 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine parasitic diseases Dihydrofolate reductase Gametocyte medicine Animals Humans Malaria Falciparum IC50 biology biology.organism_classification Virology Tetrahydrofolate Dehydrogenase Pyrimethamine 030104 developmental biology Infectious Diseases Pharmaceutical Preparations chemistry Mutation Antifolate biology.protein Folic Acid Antagonists Parasitology medicine.drug |
Zdroj: | International Journal for Parasitology. 51:635-642 |
ISSN: | 0020-7519 |
Popis: | 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. |
Databáze: | OpenAIRE |
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