Of mice and malaria mutants: unravelling the genetics of drug resistance using rodent malaria models

Carlton, Jane M.; Hayton, Karen; Cravo, Pedro Vitor Lemos; Walliker, David

doi:10.1016/s1471-4922(01)01899-2

Cited by 66 publications

(50 citation statements)

References 54 publications

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“…We report here a genetic study on S/P resistance using the rodent malaria species Plasmodium chabaudi, which is probably the best rodent model for studies on drug resistance in P. falciparum (7). Pyrimethamine resistance in P. chabaudi is known to be associated with the presence of Asn-106 in its DHFR, which is equivalent to Asn-108 in P. falciparum DHFR (9).…”

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confidence: 99%

Sulfadoxine-Pyrimethamine Resistance in the Rodent Malaria Parasite Plasmodium chabaudi

Hayton

Ranford-Cartwright

Walliker

2002

Antimicrob Agents Chemother

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We have studied resistance to sulfadoxine-pyrimethamine (S/P) in the rodent malaria parasite Plasmodium chabaudi. A stable S/P-resistant mutant, AS(50S/P), was selected by drug treatment of a clone, AS(PYR), already resistant to pyrimethamine. The sequences of the P. chabaudi dhfr and dhps genes were obtained and found to be identical in AS(50S/P) and AS(PYR), showing that resistance to S/P in AS(50S/P) was not due to additional mutations in either gene. AS(50S/P) was crossed with a drug-sensitive clone, AJ, and 16 independent recombinant progeny were obtained. These clones were phenotyped for their susceptibility to S/P and to sulfadoxine and pyrimethamine separately. Pyrimethamine resistance was invariably associated with S/P resistance, but no correlation was found between resistance to S/P and resistance to sulfadoxine. Quantitative trait locus analysis of the progeny with 31 chromosome-specific markers showed that mutant P. chabaudi dhfr, or one or more genes closely linked to it, was a major determinant of S/P resistance. In addition, the inheritance of genes on chromosomes 5 and 13 from the sensitive parent appeared to contribute to the level of resistance observed. These results demonstrate that the S/P resistance of the AS(50S/P) mutant of P. chabaudi does not involve mutation in dhps and is not due simply to a combination of two genes determining resistance to pyrimethamine and sulfadoxine separately.

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confidence: 99%

Sulfadoxine-Pyrimethamine Resistance in the Rodent Malaria Parasite Plasmodium chabaudi

Hayton

Ranford-Cartwright

Walliker

2002

Antimicrob Agents Chemother

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“…We have demonstrated that pcmdr1 amplification is associated with mefloquine resistance, but that at least one other gene must be involved, findings that are consistent with field and other laboratory studies on P. falciparum. P. chabaudi has the important advantage that drug-resistant mutants can be selected from sensitive clones in the laboratory more readily than in P. falciparum and also that crosses can be performed much more easily (7). Furthermore, the identification of genes linked to markers of resistance phenotypes will be helped by the availability of considerable genome sequence data for P. chabaudi (http://www.sanger.ac.uk/Projects/Pchabaudi/).…”

Section: Discussionmentioning

confidence: 99%

Genetics of Mefloquine Resistance in the Rodent Malaria Parasite Plasmodium chabaudi

Cravo

Carlton²,

Hunt

et al. 2003

Antimicrob Agents Chemother

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The genetic determinants of resistance to mefloquine in malaria parasites are unclear. Some studies have implied that amplification of, or mutations in, the multidrug resistance gene pfmdr1 in Plasmodium falciparum may be involved. Using the rodent malaria model Plasmodium chabaudi, we investigated the role of the orthologue of this gene, pcmdr1, in a stable mefloquine-resistant mutant, AS(15MF/3), selected from a sensitive clone. pcmdr1 exists as a single copy gene on chromosome 12 of the sensitive clone. In AS(15MF/3), the gene was found to have undergone duplication, with one copy translocating to chromosome 4. mRNA levels of pcmdr1 were higher in the mutant than in the parent sensitive clone. A partial genetic map of the translocation showed that other genes in addition to pcmdr1 had been cotranslocated. The sequences of both copies of pcmdr1 of AS(15MF/3) were identical to that of the parent sensitive clone. A cross was made between AS(15MF/3) and an unrelated mefloquine-sensitive clone, AJ. Phenotypic and molecular analysis of progeny clones showed that duplication and overexpression of the pcmdr1 gene was an important determinant of resistance. However, not all mefloquine-resistant progeny contained the duplicated gene, showing that at least one other gene was involved in resistance

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“…While resistance to CQ arose through pfcrt independent mechanisms in the rodent parasite P. chabaudi [21], human and rodent Plasmodia do share in common their mode of resistance to atovaquone, mefloquine, and pyrimethamine (reviewed in [22]). Thus, on the balance, rodent malaria models have provided informative data on mechanisms of resistance.…”

Section: Identifying Emerging Resistance Locimentioning

confidence: 99%

Advances in understanding the genetic basis of antimalarial drug resistance

Ekland

Fidock

2007

Current Opinion in Microbiology

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SummaryThe acquisition of drug resistance by Plasmodium falciparum has severely curtailed global efforts to control malaria. Our ability to define resistance has been greatly enhanced by recent advances in Plasmodium genetics and genomics. Sequencing and microarray studies have identified thousands of polymorphisms in the P. falciparum genome, and linkage disequilibrium analyses have exploited these to rapidly identify known and novel loci that influence parasite susceptibility to antimalarials such as chloroquine, quinine, and sulfadoxine-pyrimethamine. Genetic approaches have also been designed to predict determinants of in vivo resistance to new antimalarials such as the artemisinins. Transfection methodologies have defined the role of determinants including pfcrt, pfmdr1 and dhfr. This knowledge can be leveraged to develop more efficient methods of surveillance and treatment.

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Of mice and malaria mutants: unravelling the genetics of drug resistance using rodent malaria models

Cited by 66 publications

References 54 publications

Sulfadoxine-Pyrimethamine Resistance in the Rodent Malaria Parasite Plasmodium chabaudi

Sulfadoxine-Pyrimethamine Resistance in the Rodent Malaria Parasite Plasmodium chabaudi

Genetics of Mefloquine Resistance in the Rodent Malaria Parasite Plasmodium chabaudi

Advances in understanding the genetic basis of antimalarial drug resistance

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