Malaria is a deadly
infectious disease in many tropical and subtropical countries. Previous efforts to eradicate
malaria have failed, largely due to the emergence of drug-resistant parasites,
insecticide-resistant mosquitoes and, in particular, the lack of drugs or
vaccines to block parasite transmission.
ATP-binding cassette (
ABC) transporters are known to play a role in drug transport, metabolism, and resistance in many organisms, including
malaria parasites. To investigate whether a Plasmodium falciparum
ABC transporter (Pf14_0244 or PfABCG2) modulates parasite susceptibility to chemical compounds or plays a role in drug resistance, we disrupted the gene encoding PfABCG2, screened the recombinant and the wild-type 3D7 parasites against a library containing 2,816 drugs approved for human or animal use, and identified an
antihistamine (
ketotifen) that became less active against the PfABCG2-disrupted parasite in culture. In addition to some activity against asexual stages and gametocytes,
ketotifen was highly potent in blocking oocyst development of P. falciparum and the rodent parasite Plasmodium yoelii in mosquitoes. Tests of structurally related tricyclic compounds identified additional compounds with similar activities in inhibiting transmission. Additionally,
ketotifen appeared to have some activity against relapse of Plasmodium cynomolgi
infection in rhesus monkeys. Further clinical evaluation of
ketotifen and related compounds, including synthetic new derivatives, in blocking
malaria transmission may provide new weapons for the current effort of
malaria eradication.