-
New Insights into Antimalarial Chemopreventive Activity of Antifolates
- Back
Document Title
New Insights into Antimalarial Chemopreventive Activity of Antifolates
Author
Pethrak C, Posayapisit N, Pengon J, Suwanakitti N, Saeung A, Shorum M, Aupalee K, Taai K, Yuthavong Y, Kamchonwongpaisan S, Jupatanakul N
Name from Authors Collection
Scopus Author ID
37003044500
Affiliations
National Science & Technology Development Agency - Thailand; National Center Genetic Engineering & Biotechnology (BIOTEC); Chiang Mai University
Type
Article
Source Title
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
ISSN
0066-4804
Year
2022
Volume
66
Open Access
Green Published, Green Submitted
Publisher
AMER SOC MICROBIOLOGY
DOI
10.1128/aac.01538-21
Format
Abstract
Antifolates targeting dihydrofolate reductase (DHFR) are antimalarial compounds that have long been used for malaria treatment and chemoprevention (inhibition of infection from mosquitoes to humans). Despite their extensive applications, a thorough understanding of antifolate activity against hepatic malaria parasites, especially resistant parasites, has yet to be achieved. Using a transgenic Plasmodium berghei harboring quadruple mutant dhfr from Plasmodium falciparum (Pb::Pfdhfr-4M), we demonstrated that quadruple mutations on Pfdhfr confer complete chemoprevention resistance to pyrimethamine, the previous generation of antifolate, but not to a new class of antifolate designed to overcome the resistance, such as P218. Detailed investigation to pinpoint stage-specific chemoprevention further demonstrated that it is unnecessary for the drug to be present throughout hepatic development. The drug is most potent against the developmental stages from early hepatic trophozoite to late hepatic trophozoite, but it is not effective at inhibiting sporozoite and early hepatic stage development from sporozoite to early trophozoite. Our data show that P218 also inhibited the late hepatic-stage development, from trophozoite to mature schizonts to a lesser extent. With a single dose of 15 mg/kg of body weight, P218 prevented infection from up to 25,000 pyrimethamine-resistant sporozoites, a number equal to thousands of infectious mosquito bites. Additionally, the hepatic stage of malaria parasite is much more susceptible to antifolates than the asexual blood stage. This study provides important insights into the activity of antifolates as a chemopreventive therapeutic which could lead to a more efficient and cost-effective treatment regime.
Keyword
Antifolates | dihydrofolate reductase | Drug resistance | hepatic stage | Malaria | prophylaxis | sporozoite
Funding Sponsor
National Science and Technology Development Agency (NSTDA), Thailand [P-1850116]; BIOTEC research unit director initiative grant [P-1851424]
License
Copyright
Rights
Publisher
Publication Source
WOS