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pfcrt is more than the Plasmodium falciparum chloroquine resistance gene: a functional and evolutionary perspective.
Acta Trop. 2005 Jun; 94(3):170-80.AT

Abstract

Genetic, physiological and pharmacological studies are gradually revealing the molecular basis of chloroquine resistance (CQR) in the malaria parasite, Plasmodium falciparum. Recent highlights include the discovery of a key gene associated with resistance, pfcrt (Plasmodium falciparum chloroquine resistance transporter; PfCRT), encoding a novel transporter, and the characterization of global selective sweeps of haplotypes containing a K76T amino acid change within this protein. Little is known about the cellular mechanism by which resistant parasites escape the effects of chloroquine (CQ), one of the most promising drugs ever deployed, due in part to an unresolved mechanism of action. The worldwide spread of CQR argues that investigations into these mechanisms are of little value. We propose, to the contrary, that the reconstruction of the evolutionary and molecular events underlying CQR is important at many levels, including: (i) its potential to assist in the development of rational approaches to thwart future drug resistances; (ii) the stimulation of the use of CQ-like compounds in drug combinations for new therapeutic approaches; and (iii) the consideration of how the CQ-selected genome will function as the context in which current and future drugs will act, particularly in light of the many reports of multidrug resistance. The purpose of this review is to highlight, discuss and in some cases challenge the interpretations of recent findings on CQR. We consider the natural function of the PfCRT protein, the role of multiple genes and "genetic background" in the CQR mechanism, and the evolution of CQR in parasite populations. Genetic transformation techniques are improving in P. falciparum and continue to provide important insight into CQR. Here, we also discuss more subtle, yet important pharmacological approaches that may have been overlooked in a traditional "gene for drug resistance" way of thinking.

Authors+Show Affiliations

Department of Biological Sciences, 110 Mills Godwin Building/45th Street, Old Dominion University, Norfolk, VA 23529, USA. rcooper@odu.eduNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.
Review

Language

eng

PubMed ID

15866507

Citation

Cooper, Roland A., et al. "Pfcrt Is More Than the Plasmodium Falciparum Chloroquine Resistance Gene: a Functional and Evolutionary Perspective." Acta Tropica, vol. 94, no. 3, 2005, pp. 170-80.
Cooper RA, Hartwig CL, Ferdig MT. Pfcrt is more than the Plasmodium falciparum chloroquine resistance gene: a functional and evolutionary perspective. Acta Trop. 2005;94(3):170-80.
Cooper, R. A., Hartwig, C. L., & Ferdig, M. T. (2005). Pfcrt is more than the Plasmodium falciparum chloroquine resistance gene: a functional and evolutionary perspective. Acta Tropica, 94(3), 170-80.
Cooper RA, Hartwig CL, Ferdig MT. Pfcrt Is More Than the Plasmodium Falciparum Chloroquine Resistance Gene: a Functional and Evolutionary Perspective. Acta Trop. 2005;94(3):170-80. PubMed PMID: 15866507.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - pfcrt is more than the Plasmodium falciparum chloroquine resistance gene: a functional and evolutionary perspective. AU - Cooper,Roland A, AU - Hartwig,Carmony L, AU - Ferdig,Michael T, PY - 2005/5/4/pubmed PY - 2005/7/22/medline PY - 2005/5/4/entrez SP - 170 EP - 80 JF - Acta tropica JO - Acta Trop VL - 94 IS - 3 N2 - Genetic, physiological and pharmacological studies are gradually revealing the molecular basis of chloroquine resistance (CQR) in the malaria parasite, Plasmodium falciparum. Recent highlights include the discovery of a key gene associated with resistance, pfcrt (Plasmodium falciparum chloroquine resistance transporter; PfCRT), encoding a novel transporter, and the characterization of global selective sweeps of haplotypes containing a K76T amino acid change within this protein. Little is known about the cellular mechanism by which resistant parasites escape the effects of chloroquine (CQ), one of the most promising drugs ever deployed, due in part to an unresolved mechanism of action. The worldwide spread of CQR argues that investigations into these mechanisms are of little value. We propose, to the contrary, that the reconstruction of the evolutionary and molecular events underlying CQR is important at many levels, including: (i) its potential to assist in the development of rational approaches to thwart future drug resistances; (ii) the stimulation of the use of CQ-like compounds in drug combinations for new therapeutic approaches; and (iii) the consideration of how the CQ-selected genome will function as the context in which current and future drugs will act, particularly in light of the many reports of multidrug resistance. The purpose of this review is to highlight, discuss and in some cases challenge the interpretations of recent findings on CQR. We consider the natural function of the PfCRT protein, the role of multiple genes and "genetic background" in the CQR mechanism, and the evolution of CQR in parasite populations. Genetic transformation techniques are improving in P. falciparum and continue to provide important insight into CQR. Here, we also discuss more subtle, yet important pharmacological approaches that may have been overlooked in a traditional "gene for drug resistance" way of thinking. SN - 0001-706X UR - https://www.unboundmedicine.com/medline/citation/15866507/pfcrt_is_more_than_the_Plasmodium_falciparum_chloroquine_resistance_gene:_a_functional_and_evolutionary_perspective_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0001-706X(05)00085-9 DB - PRIME DP - Unbound Medicine ER -