Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase of isolates from the Amazon Region of Brazil

Vasconcelos, Kauã; Plowe, Christopher V.; Fontes, Cor Jésus Fernandes; Kyle, Dennis E.; Wirth, Dyann F.; Silva, L H Pereira da; Zalis, Mariano Gustavo

doi:10.1590/s0074-02762000000500020

Cited by 53 publications

(52 citation statements)

References 21 publications

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“…(20,26,31). It has been noted that the mutations 50R and 59R are mutually exclusive in field samples, and our results are consistent with these previous findings (7).…”

Section: Resultssupporting

confidence: 93%

Common Origin and Fixation of Plasmodium falciparum dhfr and dhps Mutations Associated with Sulfadoxine-Pyrimethamine Resistance in a Low-Transmission Area in South America

McCollum

Mueller

Villegas³

et al. 2007

Antimicrob Agents Chemother

112

150

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Recent studies indicated that sensitive parasites could increase in frequency in a population when drugs are removed, suggesting that the life span of affordable antimalarial drugs could be expanded. We studied 97 samples from Bolivar State, Venezuela, an area where sulfadoxine-pyrimethamine (SP) has not been used for 8 years due to its ineffectiveness. We characterized point mutations in two genes that have been implicated in resistance to SP, dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps). We also assayed neutral microsatellite markers around the dhfr (chromosome 4) and dhps (chromosome 8) genes and on chromosomes 2 and 3 to track the origin and spread of resistant alleles. We found that drug-resistant SP mutants are fixed in the population. Two genotypes were present in the samples, dhfr(50R/51I/108N) dhps(437G/540E/581G) (90.7%) and dhfr(51I/108N) dhps(437G/581G) (9.3%). We show a single microsatellite haplotype for all of the dhfr and dhps alleles, and the alleles at the microsatellite loci are different from those present in Africa. Thus, in these samples from Venezuela, there is a single origin for both dhfr and dhps SP-resistant alleles, and these alleles originated independently of those characterized from Africa. Furthermore, this is the first report of a "hitchhiking effect" on the genetic variation around dhps due to selection by SP using an extensive set of microsatellite markers. Our results indicate that, in areas where there is limited gene flow, the fixation of drug-resistant parasites in the population is stable, even after drug selection is relaxed.The emergence of drug-resistant Plasmodium falciparum is a serious public health problem in many countries where malaria is endemic (7, 28). Sulfadoxine-pyrimethamine (SP) is an antifolate drug commonly used to treat P. falciparum infections because of its ease of administration, affordability, and efficacy. Unfortunately, resistance to SP has been documented in many parts of the world, compromising the use of this drug for treating uncomplicated P. falciparum malaria.SP acts as an inhibitor of the P. falciparum folic acid pathway, and point mutations in the genes encoding dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) have been implicated in SP resistance (9). The dhfr(S108N) point mutation and additional mutations at codons 50, 51, 59, and 164 act synergistically to increase resistance to pyrimethamine (4, 21). Similarly, mutations at dhps codons 436, 437, 540, 581, and 613 act synergistically to increase the level of resistance to sulfadoxine (7).Recent studies following the frequency of chloroquine-resistant parasites over time showed that sensitive parasites could increase in frequency soon after the drug pressure on the parasite population was decreased (13). These results suggest that, with appro-

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“…(20,26,31). It has been noted that the mutations 50R and 59R are mutually exclusive in field samples, and our results are consistent with these previous findings (7).…”

Section: Resultssupporting

confidence: 93%

Common Origin and Fixation of Plasmodium falciparum dhfr and dhps Mutations Associated with Sulfadoxine-Pyrimethamine Resistance in a Low-Transmission Area in South America

McCollum

Mueller

Villegas³

et al. 2007

Antimicrob Agents Chemother

112

150

View full text Add to dashboard Cite

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“…Esta mutación 108 N/T se ha encontrado también en otros países de América: Colombia (20) , Perú (21) , Brasil (22) o Bolivia (15) . Lo que sugiere que el uso prolongado de pirimetamina-sulfadoxina, en estas áreas endémicas, ha llevado a la selección de estos fenotipos por "presión de selección", característica que presentan los parásitos resistentes como respuesta al uso de antimaláricos de forma prolongada.…”

Section: Discussionunclassified

Alelos mutantes asociados a la resistencia a cloroquina y sulfadoxina-pirimetamina en Plasmodium falciparum de las fronteras Ecuador-Perú y Ecuador-Colombia

Arróspide

Hijar-Guerra

Mora³

et al. 2014

Rev Peru Med Exp Salud Publica

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RESUMENSe evaluó la frecuencia de mutaciones en los genes pfCRT y DHFR/DHPS del Plasmodium falciparum asociados a la resistencia a cloroquina y sulfadoxina-pirimetamina en 83 cepas provenientes de los distritos Esmeralda y Machala ubicados en las fronteras entre Ecuador-Perú y Ecuador-Colombia durante el año 2002. Se empleó la reacción en cadena de polimerasa (PCR) convencional y sus variantes. El gen pfCRT presentó más de 90% de muestras mutantes en Esmeralda y Machala. Para el gen DHFR, el 90% de las cepas fueron muestras mutantes en Esmeralda, tres fueron mutaciones dobles y una triple; en Machala se encontró 25% de formas mutantes simples y 75% de formas mixtas (formas silvestres/mutantes). En conclusión, la resistencia a cloroquina se ha fijado en las cepas portadoras de la mutación K76T pfCRT, mientras que la impronta genética a la resistencia a pirimetamina está en evolución, principalmente en el distrito de Esmeralda.Palabras clave: Plasmodium falciparum; Resistencia bacteriana a fármacos; Cloroquina; Sulfadoxina; Pirimetamina (fuente: DeCS BIREME) MUTANT ALLELES ASSOCIATED TO CHLOROQUINE AND SULFADOXINE-PYRIMETHANIME RESISTANCE IN Plasmodium falciparum OF THE ECUADOR-PERU AND ECUADOR-COLOMBIA BORDERS ABSTRACTThe frequency of mutations in pfCRT and DHFR/DHPS genes of Plasmodium falciparum associated with resistance to chloroquine and sulfadoxine-pyrimethamine was evaluated in 83 strains from the districts of Esmeralda and Machala, located on the borders of Ecuador-Peru and Ecuador-Colombia in 2002. Polymerase chain reaction (PCR), conventional and its variants, was used. Mutations in the pfCRT gene were found in more than 90% of the samples from Esmeralda and Machala. For the DHFR gene, 90% of the strains were mutant samples from Esmeralda, 3 were double mutations and 1 was a triple mutation. In Machala, 25% were simple mutant forms and 75% mixed mutant forms (wild forms/mutant). In conclusion, resistance to chloroquine has been fixed in strains carrying K76T pfCRT mutation, whereas genetic imprinting for resistance to pyrimethamine is evolving, particularly in the district of Esmeralda.

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“…[11][12][13][14][15][16] Alleles consisting of multiple polymorphisms, such as the C50R, N51I, S108N type and the C50R, N51I, S108N, I164L type, have been identified in Brazil, Peru, and Venezuela. 17,18 In pfdhps, polymorphisms, including S436A/F, A437G, K540E, A581G, and A613S/T, have been shown to affect parasite susceptibility to sulfadoxine. 19 -21 All sulfadoxine resistance pfdhps alleles that have been identified in the Americas have the A437G polymorphism alone or in combination with K540E and/or A581G.…”

Section: Introductionmentioning

confidence: 99%

Molecular Analysis of Chloroquine and Sulfadoxine-Pyrimethamine Resistance-Associated Alleles in Plasmodium falciparum Isolates from Nicaragua

Sridaran

Rodriguez

Soto³

et al. 2014

The American Journal of Tropical Medicine and Hygiene

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Abstract. Chloroquine (CQ) is used as a first-line therapy for the treatment of Plasmodium falciparum malaria in Nicaragua. We investigated the prevalence of molecular markers associated with CQ and sulfadoxine-pyrimethamine (SP) resistance in P. falciparum isolates obtained from the North Atlantic Autonomous Region of Nicaragua. Blood spots for this study were made available from a CQ and SP drug efficacy trial conducted in 2005 and also from a surveillance study performed in 2011. Polymorphisms in P. falciparum CQ resistance transporter, dihydrofolate reductase, and dihydropteroate synthase gene loci that are associated with resistance to CQ, pyrimethamine, and sulfadoxine, respectively, were detected by DNA sequencing. In the 2005 dataset, only 2 of 53 isolates had a CQ resistance allele (CVIET), 2 of 52 had a pyrimethamine resistance allele, and 1 of 49 had a sulfadoxine resistance allele. In the 2011 dataset, none of 45 isolates analyzed had CQ or SP resistance alleles.

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Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase of isolates from the Amazon Region of Brazil

Cited by 53 publications

References 21 publications

Common Origin and Fixation of Plasmodium falciparum dhfr and dhps Mutations Associated with Sulfadoxine-Pyrimethamine Resistance in a Low-Transmission Area in South America

Common Origin and Fixation of Plasmodium falciparum dhfr and dhps Mutations Associated with Sulfadoxine-Pyrimethamine Resistance in a Low-Transmission Area in South America

Alelos mutantes asociados a la resistencia a cloroquina y sulfadoxina-pirimetamina en Plasmodium falciparum de las fronteras Ecuador-Perú y Ecuador-Colombia

Molecular Analysis of Chloroquine and Sulfadoxine-Pyrimethamine Resistance-Associated Alleles in Plasmodium falciparum Isolates from Nicaragua

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