Reversal of mefloquine and quinine resistance in Plasmodium falciparum with NP30.
Quinoline resistance in malaria is frequently compared with P-glycoprotein-mediated multidrug resistance (mdr) in mammalian cells. We have previously reported that nonylphenolethoxylates, such as NP30, are potential Plasmodium falciparum P-glycoprotein substrates and drug efflux inhibitors. We used in vitro assays to compare the ability of verapamil and NP30 to sensitize two parasite isolates to four quinolines: chloroquine (CQ), mefloquine (MF), quinine (QN), and quinidine (QD). NP30 was able to sensitize (reversal, >80%) P. falciparum to MF, QN, QD, and, to a lesser extent, CQ. The presence of 2 micro M verapamil had no effect on mefloquine resistance; however, the presence of verapamil modulated the activities of QN and QD in a manner parallel to that observed for CQ. Genetic analysis of putative quinoline resistance genes did not suggest an association between known point mutations in pfcrt and pfmdr1 and NP30 sensitization activity. We conclude that the sensitization action of NP30 is distinct both phenotypically and genotypically from that of verapamil.
Ciach
Michelle
M
Tropical Disease Unit, Toronto General Hospital, Toronto, Ontario, Canada.
Zong
Kathleen
K
Kain
Kevin C
KC
Crandall
Ian
I
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004351:Drug Resistance; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology; D015767:Mefloquine / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D011803:Quinine / Q000494:pharmacology*; D013501:Surface-Active Agents / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D000962:Antimalarials; D002121:Calcium Channel Blockers; D013501:Surface-Active Agents; D011803:Quinine; D014700:Verapamil; D015767:Mefloquine