Sulfadoxine-pyrimethamine impairs Plasmodium falciparum gametocyte infectivity and Anopheles mosquito survival.
Sulfadoxine-pyrimethamine (SP) is currently the drug of choice for intermittent preventive treatment of Plasmodium falciparum both in pregnancy and infancy. A prolonged parasite clearance time conferred by dhfr and dhps mutations is believed to be responsible for increased gametocyte prevalence in SP treated individuals. However, using a direct feeding assay in Mali, we showed that gametocytes present in peripheral venous blood post-SP treatment had reduced infectivity for Anopheles gambiae sensu stricto (ss) mosquitoes. We investigated the potential mechanisms involved in the dhfr and dhps quintuple mutant NF-135 and the single dhps 437 mutant NF-54. Concentrations of sulfadoxine (S) and pyrimethamine (P) equivalent to the serum levels of the respective drugs on day 3 (S=61 microg/ml, P=154.7 ng/ml) day 7 (S=33.8 microg/ml, P=66.6 ng/ml) and day 14 (S=14.2 microg/ml, P=15.7 ng/ml) post-SP treatment were used to study the effect on gametocytogenesis, gametocyte maturation and infectivity to Anopheles stephensi mosquitoes fed through an artificial membrane. The drugs readily induced gametocytogenesis in the mutant NF-135 strain but effectively killed the wild-type NF-54. However, both drugs impaired gametocyte maturation yielding odd-shaped non-exflagellating mature gametocytes. The concomitant ingestion of both S and P together with gametocytemic blood-meal significantly reduced the prevalence of oocyst positivity as well as oocyst density when compared to controls (P<0.001). In addition, day 3 concentrations of SP decreased mosquito survival by up to 65% (P<0.001). This study demonstrates that SP is deleterious in vitro for gametocyte infectivity as well as mosquito survival.
Malaria Research and Training Center (MRTC), Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy and Odonto-Stomatology, University of Bamako, P.O. Box 1805, Point G, Bamako, Mali.
Aminatou
A
Kone
Marga
M
van de Vegte-Bolmer
Rianne
R
Siebelink-Stoter
Geert-Jan
GJ
van Gemert
Antoine
A
Dara
Hamidou
H
Niangaly
Adrian
A
Luty
Ogobara K
OK
Doumbo
Robert
R
Sauerwein
Abdoulaye A
AA
Djimde
D000818:Animals; D000852:Anopheles / Q000187:drug effects*; D000962:Antimalarials / Q000494:pharmacology*; D004094:Dihydropteroate Synthase / Q000235:genetics / Q000378:metabolism; D004338:Drug Combinations; D004351:Drug Resistance; D005838:Genotype; D006790:Host-Parasite Interactions; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000469:parasitology; D011739:Pyrimethamine / Q000494:pharmacology*; D013413:Sulfadoxine / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism
D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine