The goal of this work is to elucidate the mechanism of drug resistance in the human malaria, P. Falciparum. Chloroquine resistance in P. falciparum is an ever present and increasing problem in world health today. In regions of Southeast Asia, Africa and South America, chloroquine, the cheapest and most efficacious antimalarial, is no longer effective for treatment and alternative, more expensive drugs must be used. Neither the definitive target of chloroquine action nor the mechanism of resistance have been elucidated. Recent evidence has demonstrated the chloroquine resistance is mediated by increased drug efflux and that this efflux can be reversed by simultaneous incubation with verapamil and other calcium channel blockers. These observations are reminiscent of a similar phenomenon in mammalian cells, namely the multi-drug resistant (mdr) phenotype. In this case, mammalian tumors often develop resistance to a broad spectrum of drugs. This resistance is mediated by the amplification of mdr genes encoding a high molecular weight plasma membrane P-glycoprotein. This P- glycoprotein shares homology with several bacterial transport proteins and the suggestion has been made that it may be an ATP- dependent efflux pump responsible for decreased accumulation of drug. We have demonstrated that P. falciparum contains at least two genes homologous to mammalian mdr genes and bacterial transport proteins and the work proposed in this grant application will test the hypothesis that a phenomenon similar to that of multi- drug resistance in mammalian cells is involved in drug resistance in Plasmodium falciparum.
| Emerson, Lyndal R; Nau, Martin E; Martin, Rodger K et al. (2002) Relationship between chloroquine toxicity and iron acquisition in Saccharomyces cerevisiae. Antimicrob Agents Chemother 46:787-96 |
