Polymorphism of the Plasmodium Falciparum Multidrug Resistance and Chloroquine Resistance Transporter Genes and in Vitro Susceptibility to Aminoquinolines in Isolates From the Peruvian Amazon

Huaman, Maria Cecilia; Roncal, Norma; Nakazawa, Shozo; Long, Ton That Ai; Gerena, Lucia; García, Coralith; Solari, Lely; Magill, Alan J.; Kanbara, Hiroji

doi:10.4269/ajtmh.2004.70.461

Cited by 28 publications

(39 citation statements)

References 30 publications

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“…No isolate analyzed in this study showed mutants Pfmdr1C1034 or pfmdr1D1042. This is in contrast with previous observations made in South America where these two alleles have been associated with high grade CQ resistance in isolates of P. falciparum [39,40 ].…”

Section: Discussioncontrasting

confidence: 56%

Chloroquine Resistant Plasmodium falciparum in Nigeria: Relationship between pfcrt and pfmdr1 Polymorphisms, In-Vitro Resistance and Treatment Outcome

Folarin

Gbotosho²,

Sowunmi³

et al. 2008

TOTMJ

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This study was designed to evaluate the association between polymorphisms in pfcrt and pfmdr1 genes and in-vitro chloroquine (CQ) sensitivity in fresh isolates of P. falciparum and patients' treatment outcome. The modified schizont inhibition assay was used to determine in-vitro sensitivity of P. falciparum. Polymorphisms in pfcrt and pfmdr1 genes were detected using nested PCR and RFLP techniques in 84 P. falciparum isolates obtained from patients with acute uncomplicated malaria.Eighty five percent (71/84) and 15% (13/84) of the parasites were resistant and sensitive in-vitro to CQ respectively. Molecular analysis showed presence of mutant pfcrtT76, pfmdr1Y86 and pfmdr1F184 alleles in 60%, 33% and 14% of the isolates respectively. There was a significant association between in-vitro and in-vivo CQ resistance (p=0.029) and also between the presence of mutant pfcrtT76+pfmdr1 Y86-Y184 haplotype and in-vitro (p=0.013) or in-vivo CQ resistance (p=0.024).Overall results from this study demonstrates that the presence of pfcrtT76+ pfmdr1 Y86-Y184 haplotype in Nigerian isolates of Plasmodium falciparum is predictive of in-vitro and in-vivo CQ resistance and therefore may be useful for monitoring resistance to this drug.

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Section: Discussioncontrasting

confidence: 56%

Chloroquine Resistant Plasmodium falciparum in Nigeria: Relationship between pfcrt and pfmdr1 Polymorphisms, In-Vitro Resistance and Treatment Outcome

Folarin

Gbotosho²,

Sowunmi³

et al. 2008

TOTMJ

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“…7 The observed triple mutations in Suriname substantiate the earlier findings of in vivo CQ-resistant P. falciparum, but the absence of the pfmdr1 N86Y mutation in both time periods was slightly unexpected. However, the reports on the correlation between the pfmdr1 N86Y mutation and in vivo and in vitro CQ resistance are not consistent, 28 and CQ-resistant isolates carrying the N86 genotype were earlier described in Peru 29 and Brazil. 24 Furthermore, reports exist that this pfmdr1 mutation is not required for CQ resistance, but rather, seems to exert an added effect on the CQ response in the presence of the K76T mutation in the pfcrt gene.…”

Section: Discussionmentioning

confidence: 98%

Molecular Surveillance as Monitoring Tool for Drug-Resistant Plasmodium falciparum in Suriname

Adhin

Labadie-Bracho²,

Bretas³

2013

The American Society of Tropical Medicine and Hygiene

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Abstract. The aim of this translational study was to show the use of molecular surveillance for polymorphisms and copy number as a monitoring tool to track the emergence and dynamics of Plasmodium falciparum drug resistance. A molecular baseline for Suriname was established in 2005, with P. falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance (pfmdr1) markers and copy number in 40 samples. The baseline results revealed the existence of a uniformly distributed mutated genotype corresponding with the fully mefloquine-sensitive 7G8-like genotype (Y184F, S1034C, N1042D, and D1246Y) and a fixed pfmdr1 N86 haplotype. All samples harbored the pivotal pfcrtK76T mutation, showing that chloroquine reintroduction should not yet be contemplated in Suriname. After 5 years, 40 samples were assessed to trace temporal changes in the status of pfmdr1 polymorphisms and copy number and showed minor genetic alterations in the pfmdr1 gene and no significant changes in copy number, thus providing scientific support for prolongation of the current drug policy in Suriname.

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“…In some parts of south-east Asia and most of South America, polymorphisms associated with resistance in one or both these genes are near-ubiquitous (Povoa et al, 1998;Zalis et al, 1998;Labbe et al, 2001;Vieira et al, 2001;Contreras et al, 2002;Cortese et al, 2002;Lopes et al, 2002;Vinayak et al, 2003;Casey et al, 2004;Huaman et al, 2004;Vathsala et al, 2004), a situation attributed to relatively higher levels of symptomatic infections and consequently increased levels of drug usage (Warhurst and Duraisingh, 2001;Hastings, 2003). In such circumstances, cessation of CQ use would not automatically lead to an expanded population of parasites carrying the wildtype alleles as the possibility of mixed infections, and thus competition between resistant and sensitive parasites, would be minimal.…”

Section: Discussionmentioning

confidence: 99%

pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum

Hayward

Saliba

Kirk

2005

Molecular Microbiology

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SummaryEfforts to control malaria worldwide have been hindered by the development and expansion of parasite populations resistant to many first-line antimalarial compounds. Two of the best-characterized determinants of drug resistance in the human malaria parasite Plasmodium falciparum are pfmdr1 and pfcrt , although the mechanisms by which resistance is mediated by these genes is still not clear. In order to determine whether mutations in pfmdr1 associated with chloroquine resistance affect the capacity of the parasite to persist when drug pressure is removed, we conducted competition experiments between P. falciparum strains in which the endogenous pfmdr1 locus was modified by allelic exchange. In the absence of selective pressure, the component of chloroquine resistance attributable to mutations at codons 1034, 1042 and 1246 in the pfmdr1 gene also gave rise to a substantial fitness cost in the intraerythrocytic asexual stage of the parasite. The loss of fitness incurred by these mutations was calculated to be 25% with respect to an otherwise genetically identical strain in which wild-type polymorphisms had been substituted at these three codons. At least part of the fitness loss may be attributed to a diminished merozoite viability. These in vitro results support recent in vivo observations that in several countries where chloroquine use has been suspended because of widespread resistance, sensitive strains are re-emerging.

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Polymorphism of the Plasmodium Falciparum Multidrug Resistance and Chloroquine Resistance Transporter Genes and in Vitro Susceptibility to Aminoquinolines in Isolates From the Peruvian Amazon

Cited by 28 publications

References 30 publications

Chloroquine Resistant Plasmodium falciparum in Nigeria: Relationship between pfcrt and pfmdr1 Polymorphisms, In-Vitro Resistance and Treatment Outcome

Chloroquine Resistant Plasmodium falciparum in Nigeria: Relationship between pfcrt and pfmdr1 Polymorphisms, In-Vitro Resistance and Treatment Outcome

Molecular Surveillance as Monitoring Tool for Drug-Resistant Plasmodium falciparum in Suriname

pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum

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