Genome comparison of progressively drug resistant Plasmodium falciparum lines derived from drug sensitive clone

Toteja, Ravi; Nair, Lathika; Bhasin, V K

doi:10.1590/s0074-02762001000300025

Cited by 6 publications

(5 citation statements)

References 19 publications

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“…This could explain the detection in the isolates analyzed in our study of the TYIN, TYINGE, and TYIRNGE haplotypes. The circulation of these isolates harboring multiple CQ and SP resistance mutations in an endemic area is not to be underestimated, because, as previously reported, 57 selection of a high degree of resistance toward a given antimalarial, in this case the pyrimethamine, could be accompanied by increase of a total number of mutations in P. falciparum . Hence, the Sudanese isolates of P. falciparum carrying multiple mutations are expected to be somewhat resistant and in case of accumulation of further mutations could become really difficult to be treated.…”

Section: Discussionmentioning

confidence: 71%

Frequency Distribution of Antimalarial Drug Resistance Alleles among Plasmodium falciparum Isolates from Gezira State, Central Sudan, and Gedarif State, Eastern Sudan

Menegon

Talha²,

Severini³

et al. 2010

The American Society of Tropical Medicine and Hygiene

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In 2004, Sudan adopted artesunate + sulfadoxine/pyrimethamine (SP) combination as the first-line drug, in response to the high level of falciparum resistance to antimalarials. In 2007, a molecular study on antimalarial resistance linked genes, pfcrt, pfmdr1, pfdhfr, pfdhps, and pfATPase6, was conducted on 198 isolates from central and eastern Sudan. We observed a high frequency of point mutations at almost all loci analyzed, mainly of pfcrt 76T (72.7%), pfdhfr 51I (75.3%), and pfdhfr 108N (72.7%) alleles. The MARK III in vitro test for chloroquine sensitivity in 45 P. falciparum isolates showed that 37.8% of the isolates were low resistant and 6.7% were fully resistant. This study represents the most recent molecular investigation on antimalarial resistance in this area after the adoption of artemisinin-based combination therapy (ACT), and underlines the importance of the analysis of SP resistance evolution to monitor the efficacy of ACT therapy in endemic areas.

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Section: Discussionmentioning

confidence: 71%

Frequency Distribution of Antimalarial Drug Resistance Alleles among Plasmodium falciparum Isolates from Gezira State, Central Sudan, and Gedarif State, Eastern Sudan

Menegon

Talha²,

Severini³

et al. 2010

The American Society of Tropical Medicine and Hygiene

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“…6 Unfortunately, resistance to its action has quickly developed, and is now widespread: chloroquine can not be used anymore in Southern Asia and in many countries in Latin America. 6,16,17 Chloroquine still plays an important role in the treatment of acute, uncomplicated P. falciparum infections in some countries where transmission is intense, notably in tropical Africa. 15 Amodiaquine belongs to the same family of choroquine, but is less efficient, more expensive and more toxic.…”

Section: Chemotherapy For Falciparum Malariamentioning

confidence: 99%

“…56 There are various studies showing unequivocally that antifolate-resistance in pfDHFR, either in the field or in laboratory, is caused by the mutations described. 16,17,43,44,[53][54][55][56][57][58][59][60][61][62][63][64][65] An attempt to delay (but not overcome) this problem consists in the use of combinations of two or more drugs to treat malaria, a technique known as combination therapy. Such combinations usually involve a Type 1 and a Type 2 antifolate, such as PS, pyrimethamine-dapsone (commercially known as Maloprim) and chlorproguanildapsone (the first one is the prodrug for the antifolate chlorcycloguanil).…”

Section: Pfdhfr Resistance To Antifolatesmentioning

confidence: 99%

Type 2 antifolates in the chemotherapy of falciparum malaria

Delfino¹,

Santos-Filho²,

Figueroa‐Villar³

2002

J. Braz. Chem. Soc.

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Cerca de 40% da população mundial está exposta à malária, o que resulta na morte de mais de dois milhões de pessoas por ano na África, América Latina, Ásia Meridional e Oceania. A forma mais grave de malária em humanos é causada pelo protozoário Plasmodium falciparum. A quimioterapia ainda é uma das principais estratégias de controle deste parasita. Muitos dos antimalariais atuam inibindo a enzima di-hidrofolato redutase (DHFR), o que resulta na morte do protozoário. Contudo, o desenvolvimento de resistência tem reduzido a eficiência dos antifolatos como antimalariais. Este fenômeno foi relacionado à ocorrência de mutações na di-hidrofolato redutase do parasita. Este artigo faz uma revisão rapida de algumas características da malária falciparum, seguida de uma revisão extensiva da di-hidrofolato redutase do P. falciparum e das mutações relacionadas à resistência a antifolatos. About 40% of the world population is exposed to malaria, which results in the death of over 2 million people per year in Africa, Latin America, Southern Asia and Oceania. The most severe type of malaria in humans is caused by the protozoan parasite Plasmodium falciparum. Chemotherapy is still one of the main control strategies for this parasite. Many of the antimalarials act by inhibiting the enzyme dihydrofolate reductase (DHFR), resulting in protozoan death. However, the development of drug resistance is reducing the efficiency of antifolates as antimalarials. This phenomenon has been linked to the occurrence of mutations in the dihydrofolate reductase of the parasite. This article includes a preliminary review of some of the features of falciparum malaria, followed by a more extensive review of the dihydrofolate reductase of P. falciparum and the mutations related to antifolate resistance.

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“…This phenomenon has rendered other times wonderful antimalarials, such as chloroquine, completely useless in several regions. [5][6][7] Also, it should be expected that resistance should eventually rise for any new drug that we develop in the future, thus making the search of new antimalarial chemotherapy a continuous task for the scientific community.…”

Section: Introductionmentioning

confidence: 99%

A complete model of the Plasmodium falciparum bifunctional enzyme dihydrofolate reductase-thymidylate synthase: a model to design new antimalarials

França¹,

Medeiros²,

Santos³

et al. 2004

J. Braz. Chem. Soc.

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É proposto um modelo teórico para a pfDHFR-TS que inclui os 55 aminoácidos que não foram contemplados no modelo cristalográfico. O cálculo do potencial eletrostático sobre a superfície do modelo, revelou uma região contínua de potencial positivo conectando os dois sítios ativos, sugerindo um mecanismo otimizado de transporte de dihidrofolato.We propose a theoretical model for pfDHFR-TS, which includes the 55 aminoacid residues ignored in the crystallographic model. The electrostatic potential calculation on the model surface revealed a continuous positive potential region between the two active sites, suggesting an optimized mechanism for dihydrofolate transport. Keywords: malaria, homology modeling, DHFR-TS, optimized substrate transport, Plasmodium falciparum IntroductionMalaria is one of the most serious widespread parasitic diseases in humans. Nowadays, at least 300 million people are infected by malaria every year, with something in between 2 and 3 million deaths. To worsen the situation, the population that lives in endemic areas is about 2 billion people or 40% of the world population.1 It is possible that the rise in Earth temperature will eventually increase the endemic areas to include greater extensions of Europe and North America. In some parts of Africa, 10% of the deaths of children less than five years old are due to the direct effects of malaria. In fact, the actual epidemic of malaria makes it impossible to calculate the contribution of this disease to the mortality rate of children of this age due to other sickness. 2 The World Health Organization (WHO) estimates that 3,000 children under 5 years old die of malaria in Africa every day, 3 a situation that Mankind should not tolerate. In addition and frequently overlooked in the case of malaria caused by Plasmodium falciparum, there is considerable morbidity associated with this disease that manifests as chronic severe anemia in children and adults. In Brazil, the most important endemic areas of malaria are situated in Amazonian Region, where this disease is one of the major hindrances to the progress of the region, leading to 300,000 to 400,000 new reported cases every year. 4Malaria is a disease of the poorest regions of the planet, and because of this, the interest of the major pharmaceutical companies in the development of economically feasible chemotherapy is very low or does not exist. In fact, the strategies used against malaria, like chemotherapy and the use of insecticides, are often not accessible to the populations of the endemic areas due to economic and social reasons.One of the major obstacles to the control of malaria is the rapid spread of parasite resistance to the current available chemotherapy and of the mosquito vector to insecticides. This phenomenon has rendered other times wonderful antimalarials, such as chloroquine, completely useless in several regions.5-7 Also, it should be expected that resistance should eventually rise for any new drug that we develop in the future, thus making the search of new antimalarial chemother...

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Genome comparison of progressively drug resistant Plasmodium falciparum lines derived from drug sensitive clone

Cited by 6 publications

References 19 publications

Frequency Distribution of Antimalarial Drug Resistance Alleles among Plasmodium falciparum Isolates from Gezira State, Central Sudan, and Gedarif State, Eastern Sudan

Frequency Distribution of Antimalarial Drug Resistance Alleles among Plasmodium falciparum Isolates from Gezira State, Central Sudan, and Gedarif State, Eastern Sudan

Type 2 antifolates in the chemotherapy of falciparum malaria

A complete model of the Plasmodium falciparum bifunctional enzyme dihydrofolate reductase-thymidylate synthase: a model to design new antimalarials

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