Multiple drugs compete for transport via the P. falciparum chloroquine resistance transporter at distinct but interdependent sites [Microbiology]

November 6th, 2014 by Bellanca, S., Summers, R. L., Meyrath, M., Dave, A., Nash, M. N., Dittmer, M., Sanchez, C. P., Stein, W. D., Martin, R. E., Lanzer, M.

Mutations in the chloroquine resistance transporter (PfCRT) are a major determinant of drug resistance in the malaria parasite Plasmodium falciparum. We have previously shown that mutant PfCRT transports the antimalarial drug chloroquine away from its target, whereas the wild-type form of PfCRT does not. However, little is understood about the transport of other drugs via PfCRT or the mechanism by which PfCRT recognizes different substrates. Here we show that mutant PfCRT also transports quinine, quinidine, and verapamil, indicating that the protein behaves as a multi-drug resistance carrier. Detailed kinetic analyses revealed that chloroquine and quinine compete for transport via PfCRT in a manner that is consistent with mixed-type inhibition. Moreover, our analyses suggest PfCRT accepts chloroquine and quinine at distinct but antagonistically interacting sites. We also found verapamil to be a partial mixed-type inhibitor of chloroquine transport via PfCRT, further supporting the idea that PfCRT possesses multiple substrate-binding sites. Our findings provide new mechanistic insights into the workings of PfCRT which could be exploited to design potent inhibitors of this key mediator of drug resistance.
  • Posted in Journal of Biological Chemistry, Publications
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