We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Verapamil-Sensitive Transport of Quinacrine and Methylene Blue via the Plasmodium falciparum Chloroquine Resistance Transporter Reduces the Parasite's Susceptibility to these Tricyclic Drugs.
- Authors
van Schalkwyk, Donelly A.; Nash, Megan N.; Shafik, Sarah H.; Summers, Robert L.; Lehane, Adele M.; Smith, Peter J.; Martin, Rowena E.
- Abstract
<bold>Background: </bold>It is becoming increasingly apparent that certain mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) alter the parasite's susceptibility to diverse compounds. Here we investigated the interaction of PfCRT with 3 tricyclic compounds that have been used to treat malaria (quinacrine [QC] and methylene blue [MB]) or to study P. falciparum (acridine orange [AO]).<bold>Methods: </bold>We measured the antiplasmodial activities of QC, MB, and AO against chloroquine-resistant and chloroquine-sensitive P. falciparum and determined whether QC and AO affect the accumulation and activity of chloroquine in these parasites. We also assessed the ability of mutant (PfCRT(Dd2)) and wild-type (PfCRT(D10)) variants of the protein to transport QC, MB, and AO when expressed at the surface of Xenopus laevis oocytes.<bold>Results: </bold>Chloroquine resistance-conferring isoforms of PfCRT reduced the susceptibility of the parasite to QC, MB, and AO. In chloroquine-resistant (but not chloroquine-sensitive) parasites, AO and QC increased the parasite's accumulation of, and susceptibility to, chloroquine. All 3 compounds were shown to bind to PfCRT(Dd2), and the transport of QC and MB via this protein was saturable and inhibited by the chloroquine resistance-reverser verapamil.<bold>Conclusions: </bold>Our findings reveal that the PfCRT(Dd2)-mediated transport of tricyclic antimalarials reduces the parasite's susceptibility to these drugs.
- Subjects
VERAPAMIL; QUINACRINE; MALARIA treatment; DRUG resistance; PLASMODIUM falciparum; METHYLENE blue; CHLOROQUINE; MICROBIAL sensitivity tests; THERAPEUTICS; PROTOZOA; PROTEIN metabolism; ANTIMALARIALS; BIOLOGICAL transport; GENES; GENETICS; OVUM; VERTEBRATES; MEMBRANE transport proteins; PHARMACODYNAMICS
- Publication
Journal of Infectious Diseases, 2016, Vol 213, Issue 5, p800
- ISSN
0022-1899
- Publication type
journal article
- DOI
10.1093/infdis/jiv509