pfcrt is more than the Plasmodium falciparum chloroquine resistance gene: a functional and evolutionary perspective

Cooper, Roland A.; Hartwig, Carmony L.; Ferdig, Michael T.

doi:10.1016/j.actatropica.2005.04.004

Cited by 89 publications

(66 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Global distribution of CQR Pfcrt and Pfmdr1 alleles. Our results, together with the results of several previous studies, suggest that although various CQR Pfcrt and Pfmdr1 alleles predominate in P. falciparum populations in different geographic regions and countries, none of these alleles is restricted to any one particular location (2,13,14,25,34,58,61). Instead, a variety of alleles can be found in many populations worldwide.…”

Section: Discussionsupporting

confidence: 50%

Discordant Patterns of Genetic Variation at Two Chloroquine Resistance Loci in Worldwide Populations of the Malaria Parasite Plasmodium falciparum

Mehlotra

Mattera

Bockarie

et al. 2008

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Mutations in the chloroquine resistance (CQR) transporter gene of Plasmodium falciparum (Pfcrt; chromosome 7) play a key role in CQR, while mutations in the multidrug resistance gene (Pfmdr1; chromosome 5) play a significant role in the parasite's resistance to a variety of antimalarials and also modulate CQR. To compare patterns of genetic variation at Pfcrt and Pfmdr1 loci, we investigated 460 blood samples from P. falciparuminfected patients from four Asian, three African, and three South American countries, analyzing microsatellite (MS) loci flanking Pfcrt (five loci [ϳ40 kb]) and Pfmdr1 (either two loci [ϳ5 kb] or four loci [ϳ10 kb]). CQR Pfmdr1 allele-associated MS haplotypes showed considerably higher genetic diversity and higher levels of subdivision than CQR Pfcrt allele-associated MS haplotypes in both Asian and African parasite populations. However, both Pfcrt and Pfmdr1 MS haplotypes showed similar levels of low diversity in South American parasite populations. Median-joining network analyses showed that the Pfcrt MS haplotypes correlated well with geography and CQR Pfcrt alleles, whereas there was no distinct Pfmdr1 MS haplotype that correlated with geography and/or CQR Pfmdr1 alleles. Furthermore, multiple independent origins of CQR Pfmdr1 alleles in Asia and Africa were inferred. These results suggest that variation at Pfcrt and Pfmdr1 loci in both Asian and African parasite populations is generated and/or maintained via substantially different mechanisms. Since Pfmdr1 mutations may be associated with resistance to artemisinin combination therapies that are replacing CQ, particularly in Africa, it is important to determine if, and how, the genetic characteristics of this locus change over time.

show abstract

Section: Discussionsupporting

confidence: 50%

Discordant Patterns of Genetic Variation at Two Chloroquine Resistance Loci in Worldwide Populations of the Malaria Parasite Plasmodium falciparum

Mehlotra

Mattera

Bockarie

et al. 2008

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…The CQ-sensitive HON strain showed increased sensitivity to all CA tested, other than QN, compared to the CQ-resistant controls 7G8 and Dd2. The Dd2 and 106/1 76T lines both carry the K76T mutation ubiquitously found in CQ-resistant isolates, differing only by a threonine-to-isoleucine substitution at PfCRT position 356 (15). Not surprisingly, the responses for the two lines were similar for all CA.…”

Section: I-369fmentioning

confidence: 63%

Mutation in the Plasmodium falciparum CRT Protein Determines the Stereospecific Activity of Antimalarial Cinchona Alkaloids

Griffin

Hoke

Samarakoon

et al. 2012

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

eThe Cinchona alkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (؊)-quinine and (؉)-quinidine. The potency of (؉)-isomers is greater than the (؊)-isomers in vitro and in vivo against Plasmodium falciparum malaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparum chloroquine resistance transporter), reversed the normal potency order of quinine and quinidine toward P. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured the in vitro susceptibility of eight clonal lines of P. falciparum derived from the 106/1 strain, each containing a unique pfcrt allele, to four Cinchona stereoisomer pairs: quinine and quinidine; cinchonidine and cinchonine; hydroquinine and hydroquinidine; 9-epiquinine and 9-epiquinidine. Stereospecific potency of the Cinchona alkaloids was associated with changes in charge and hydrophobicity of mutable PfCRT amino acids. In isogenic chloroquine-resistant lines, the IC 50 ratio of (؊)/(؉) CA pairs correlated with side chain hydrophobicity of the position 76 residue. Second-site PfCRT mutations negated the K76I stereospecific effects: charge-change mutations C72R or Q352K/R restored potency patterns similar to the parent K76 line, while V369F increased susceptibility to the alkaloids and nullified stereospecific differences between alkaloid pairs. Interactions between key residues of the PfCRT channel/transporter with (؊) and (؉) alkaloids are stereospecifically determined, suggesting that PfCRT binding plays an important role in the antimalarial activity of quinine and other Cinchona alkaloids.A lkaloids from the Cinchona tree, exemplified by quinine (QN) and quinidine (QD), have proven to be an important source of antimalarial therapies, especially after resistance to chloroquine (CQ) emerged. QN remains a first-line drug in the treatment of severe malaria in many parts of the world, even with increased use of artemisinin-based combination therapies (70). The Cinchona alkaloids (CA) are aryl amino alcohols where the aryl group is a quinoline (quinoline aminoalcohols). They have four chiral centers, two of which, C-8 and C-9, can have different configurations (66) (Fig. 1). Among the pharmacologically active 8,9-erythro isomers, QN, hydroquinine (HQN), and cinchonidine (CD) all present the S configuration around C-8 and the R configuration at C-9 and are levorotatory (rotate plane polarized light in an anticlockwise [Ϫ] direction). The reverse ordering, R at C-8 and S at C-9, occurs in the respective dextrorotatory (rotate plane polarized light in a clockwise [ϩ] direction) diastereomers, QD, hydroquinidine (HQD), and cinchonine (CN). The 8,9-threo diastereomers 9-epiquinine (EQN) and 9-epiquinidine (EQD) are 8S, 9S, and 8R, 9R, respectively.Against Plasmodium falciparum, the CA diastereomer pairs have a well-established in ...

show abstract

“…Investigation of pfcrt K76T, A220S, Q271E, N326S, I356T, and R371I and pfmdr1 N86Y mutation of isolates from Thailand has showed distinct patterns and prevalence depending on the period under investigation and study areas with selection history, but the K76T change appears necessary for the resistance phenotype and is the most reliable molecular marker of chloroquine resistance among the various mutations. 31 The prevalence of pfcrt and pfmdr1 mutations was found to be 100% and 9%, respectively, in isolates obtained during 1988-1993 and 2003 from the Thailand-Cambodia border. 32 Isolates obtained from the Thailand-Myanmar border during 2002-2004 showed a pfcrt 76T mutation frequency of 99% and a pfmdr1 86Y mutation frequency of 22.2%, 33 and isolates obtained from the same area during 2010 showed a pfcrt 76T mutation frequency of 96% and a pfmdr1 86Y mutation frequency of 8%.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of Molecular Markers of Antimalarial Drug Resistance and Relationship with Artesunate-Mefloquine Combination Therapy in Patients with Uncomplicated Plasmodium falciparum Malaria in Thailand

Muhamad

Phompradit

Sornjai³

et al. 2011

The American Society of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

Abstract. The aim of this study was to investigate the association between genetic polymorphisms of Plasmodium falciparum chloroquine resistance transporter ( pfcrt ), P. falciparum multidrug resistance 1 ( pfmdr1 ), and P. falciparum ATPase ( pfatp6 ) and clinical outcome after a three-day mefloquine-artesunate combination therapy in 134 patients with uncomplicated Plasmodium falciparum malaria in an area with multidrug resistance along the Thailand-Myanmar border. Analysis of gene mutation and amplification were performed by nested real-time polymerase chain reaction and SYBR Green I real-time polymerase chain reaction, respectively. The mutation for pfcrt (codons 76, 220, 271, 326, 356, and 371) was found in all isolates (100%), whereas no mutation of pfmdr1 (codon 86) and pfatp6 (codons 37, 693, 769, 898) was found. The Pfmdr1 copy number was significantly higher in isolates with recrudescence (median number = 2.44) compared with a sensitive response (median number = 1.44). The gene copy number was also found to be significantly higher in paired isolates collected before treatment and at the time of recrudescence. All isolates carried one pfatp6 gene copy.

show abstract

pfcrt is more than the Plasmodium falciparum chloroquine resistance gene: a functional and evolutionary perspective

Cited by 89 publications

References 63 publications

Discordant Patterns of Genetic Variation at Two Chloroquine Resistance Loci in Worldwide Populations of the Malaria Parasite Plasmodium falciparum

Discordant Patterns of Genetic Variation at Two Chloroquine Resistance Loci in Worldwide Populations of the Malaria Parasite Plasmodium falciparum

Mutation in the Plasmodium falciparum CRT Protein Determines the Stereospecific Activity of Antimalarial Cinchona Alkaloids

Polymorphisms of Molecular Markers of Antimalarial Drug Resistance and Relationship with Artesunate-Mefloquine Combination Therapy in Patients with Uncomplicated Plasmodium falciparum Malaria in Thailand

Contact Info

Product

Resources

About