scholarly journals Prevalence of Mutations Associated with Higher Levels of Sulfadoxine-Pyrimethamine Resistance in Plasmodium falciparum Isolates from Car Nicobar Island and Assam, India

2006 ◽  
Vol 50 (11) ◽  
pp. 3934-3938 ◽  
Author(s):  
Anwar Ahmed ◽  
Vanshika Lumb ◽  
Manoj K. Das ◽  
Vas Dev ◽  
Wajihullah ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Dihydrofolate Reductase ◽  
Drug Policy ◽  
Uttar Pradesh ◽  
Nicobar Island ◽  
Wild Type

ABSTRACT To assess sulfadoxine and pyrimethamine resistance (SPR), we describe here the dihydropteroate synthetase (DHPS) mutations among the Plasmodium falciparum isolates in which dihydrofolate reductase (DHFR) mutations had recently been described by us (A. Ahmed, M. K. Das, V. Dev, M. A. Saifi, Wajihullah, and Y. D. Sharma, Antimicrob. Agents Chemother. 50:1546-1549, 2006). A majority of isolates from Car Nicobar island showed double DHPS mutations, whereas a majority of isolates from Uttar Pradesh (U.P.) and Assam contained the wild-type DHPS. Based on DHFR-DHPS mutations, the expected level of SPR was lowest in U.P., higher in Assam, and highest in Car Nicobar, suggesting that a region-wise drug policy is needed in India.

scholarly journals Kenyan Plasmodium falciparum Field Isolates: Correlation between Pyrimethamine and Chlorcycloguanil Activity In Vitro and Point Mutations in the Dihydrofolate Reductase Domain

1998 ◽  
Vol 42 (1) ◽  
pp. 164-169 ◽  
Author(s):  
A. Nzila-Mounda ◽  
E. K. Mberu ◽  
C. H. Sibley ◽  
C. V. Plowe ◽  
P. A. Winstanley ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Dihydrofolate Reductase ◽  
Drug Response ◽  
Point Mutations ◽  
Distinct Group ◽  
Wild Type ◽  
Field Isolates ◽  
Vitro Data ◽  
In Vitro Data

ABSTRACT Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC50s) for PM and CCG (P< 0.01) and their DHFR genotypes. The first group consists of wild-type isolates with mean PM and CCG IC50s of 3.71 ± 6.94 and 0.24 ± 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC50s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC50s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease (P < 0.01) of SD and DDS susceptibility in these triple mutants. Our data show that more than 92% of Kenyan field isolates have undergone at least one point mutation associated with a decrease in PM activity. These findings are of great concern because they may indicate imminent PM-SD failure, and there is no affordable antimalarial drug to replace PM-SD (Fansidar).

scholarly journals Characteristics of Genetic Hitchhiking around Dihydrofolate Reductase Gene Associated with Pyrimethamine Resistance in Plasmodium falciparum Isolates from India

2009 ◽  
Vol 53 (12) ◽  
pp. 5173-5180 ◽  
Author(s):  
Vanshika Lumb ◽  
Manoj K. Das ◽  
Neeru Singh ◽  
Vas Dev ◽  
Wajihullah ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Dihydrofolate Reductase ◽  
Target Genes ◽  
Indian Subcontinent ◽  
Point Mutations ◽  
Uttar Pradesh ◽  
Southeast Asian ◽  
Genetic Hitchhiking ◽  
Origin And Evolution ◽  
Geographical Regions

ABSTRACT Sulfadoxine-pyrimethamine (SP) resistance in Plasmodium falciparum has been widespread across continents, causing the major hurdle of controlling malaria. Resistance is encoded mainly by point mutations in P. falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) target genes. To study the origin and evolution of pyrimethamine resistance on the Indian subcontinent, microsatellite markers flanking the pfdhfr gene were mapped. Here we describe the characteristics of genetic hitchhiking around the pfdhfr gene among 190 P. falciparum isolates. These isolates were collected from five different geographical regions of India (Uttar Pradesh, Madhya Pradesh, Assam, Orissa, and Andaman and Nicobar Islands) where malarial transmission rates and levels of drug resistance vary across regions. Among the isolates, we observed a significant reduction in genetic variation in the ±20-kb vicinity of the mutant pfdhfr alleles due to hitchhiking. This reduction in genetic diversity was more prominent around quadruple pfdhfr alleles (heterozygosity [H e] = 0.23) than around double (H e = 0.365) and single (H e = 0.465) mutant alleles. Asymmetry in the selective sweep flanking the pfdhfr alleles was observed with regional isolates, emphasizing the drug usage with the parasite population. All the pfdhfr alleles share a single microsatellite haplotype and seem to have originated from a single progenitor similar to that of Southeast Asian (Thailand) pfdhfr mutants. Results of the present study also indicate that the emergence of drug-resistant alleles is a recent phenomenon in India compared to Southeast Asian countries.

scholarly journals Quadruple Mutations in Dihydrofolate Reductase of Plasmodium falciparum Isolates from Car Nicobar Island, India

2006 ◽  
Vol 50 (4) ◽  
pp. 1546-1549 ◽  
Author(s):  
Anwar Ahmed ◽  
Manoj K. Das ◽  
Vas Dev ◽  
Muheet A. Saifi ◽  
Wajihullah ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Dihydrofolate Reductase ◽  
Malaria Control ◽  
Control Program ◽  
Nicobar Island ◽  
Drug Pressure ◽  
Malaria Control Program ◽  
Very High

ABSTRACT Quadruple mutations in the Plasmodium falciparum dihydrofolate reductase (PFDHFR) enzyme give rise to the highest level of pyrimethamine resistance leading to treatment failures. We describe here the presence of these quadruple mutations in a majority of P. falciparum isolates from Car Nicobar (Andaman and Nicobar) Island, India. Isolates from the mainland, however, continue to show a prevalence of double PFDHFR mutations and some with triple but none with quadruple mutations. In conclusion, the antifolate drug pressure is very high in the island, which should be a cause of concern for the malaria control program in the country.

Discovery of traditional Chinese medicine derived compounds as wild type and mutant Plasmodium falciparum dihydrofolate reductase inhibitors: Induced fit docking and ADME studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Opeyemi Iwaloye ◽  
Olusola Olalekan Elekofehinti ◽  
Babatomiwa Kikiowo ◽  
Toyin Mary Fadipe ◽  
Moses Orimoloye Akinjiyan ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Dihydrofolate Reductase ◽  
Active Sites ◽  
Wild Type ◽  
Induced Fit Docking ◽  
Induced Fit ◽  
Lipinski’S Rule ◽  
Drug Candidates

Background: In a bid to come up with effective compounds as inhibitors in antimalarial treatment, we built a library containing about 2,000 traditional Chinese medicine(TCM)-derived compounds retrieved from TCM Data-base@Taiwan. The active sites of both the wild type and mutant Plasmodium falciparum dihydrofolate reductase (pfDHFR) were explored using computational tools. pfDHFR, one of the prime drug targets in the prevention of malaria infection induced by the female anopheles mosquito has continued to coffer resistance to drugs (antifolates) due to mutation in some of the key amino acid residues crucial for its inhibition. Results: We utilized virtual throughput screening and glide XP docking to screen the compounds, and 8 compounds were found to have promising docking score with both the wild type and mutant pfDHFR. They were further subjected to induced fit docking (IFD) to affirm their inhibitory potency. The ADME properties and biological activity spectrum of the com-pounds were also considered. Inspection of the inhibition profile of the compounds demonstrated that a number of the com-pounds form intermolecular interaction with ASP54, ILE14, LEU164, SER108/ASN108, ARG122 and ASP58. Majority of the compounds are considered to be drug candidates due to their antiprotozoal activities and accordance with Lipinski’s rule of five (ROF). Conclusion: The outcome of the present study should further be investigated to attest the efficacy of these compounds as better drug candidates than the antifolates.

scholarly journals Conflicting Requirements of Plasmodium falciparum Dihydrofolate Reductase Mutations Conferring Resistance to Pyrimethamine-WR99210 Combination

2007 ◽  
Vol 51 (12) ◽  
pp. 4356-4360 ◽  
Author(s):  
Deanpen Japrung ◽  
Ubolsree Leartsakulpanich ◽  
Sudsanguan Chusacultanachai ◽  
Yongyuth Yuthavong
Keyword(s):  
Plasmodium Falciparum ◽  
Dihydrofolate Reductase ◽  
Enzyme Inhibitor ◽  
Random Mutagenesis ◽  
Wild Type ◽  
Resistance Mutations ◽  
Inhibitor Binding ◽  
Drug Classes ◽  
Antifolate Resistance ◽  
Resistance Mutants

ABSTRACT Plasmodium falciparum strains bearing quadruple mutations of dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) at codons 51, 59, 108, and 164 are highly resistant to pyrimethamine (PYR), a diaminopyrimidine, but sensitive to WR99210 (WR), a cycloguanil analog, suggesting different enzyme-inhibitor binding interactions. A combination of these inhibitors to delay the onset of antifolate resistance is proposed. Using error-prone PCR, libraries of random mutants of wild-type PfDHFR and PfDHFR-TS were generated and used to transform Escherichia coli, and transformants were then selected for PYR or WR resistance. Mutants highly resistant to either PYR or WR were also generated from libraries obtained from further random mutagenesis of quadruple mutants (QM) with mutations in PfDHFR or PfDHFR-TS. For reversion mutants carrying altered residues I51N, N108S, and L164I, a further mutation of D54N was required to achieve resistance against WR, but these mutants regained sensitivity to PYR. When a combination of PYR and WR was used, fewer resistant mutants were generated from both mutant libraries using the QM gene templates. The effectiveness of the drug combination in reducing the appearance of resistance mutations is likely due to conflicting requirements for mutations conferring resistance to the two drugs. Thus, a combination of inhibitors from these two drug classes should be effective in impeding the emergence of P. falciparum resistance to antifolates.

scholarly journals Evaluation of the Activities of Pyrimethamine Analogs against Plasmodium vivax and Plasmodium falciparum Dihydrofolate Reductase-Thymidylate Synthase Using In Vitro Enzyme Inhibition and Bacterial Complementation Assays

2006 ◽  
Vol 50 (11) ◽  
pp. 3631-3637 ◽  
Author(s):  
Sasinee Bunyarataphan ◽  
Ubolsree Leartsakulpanich ◽  
Supannee Taweechai ◽  
Bongkoch Tarnchompoo ◽  
Sumalee Kamchonwongpaisan ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Vivax ◽  
Enzyme Inhibition ◽  
Dihydrofolate Reductase ◽  
Thymidylate Synthase ◽  
Enzyme Inhibitors ◽  
Side Chain ◽  
Wild Type ◽  
Continuous Culture System

ABSTRACT Pyrimethamine analogs were examined as potential agents against vivax malaria using a bacterial surrogate system carrying Plasmodium vivax dihydrofolate reductase-thymidylate synthase (PvDHFR-TS), in which the PvDHFR complemented chemically knocked out host dihydrofolate reductase. The system was initially tested with P. falciparum dihydrofolate reductase-thymidylate synthase and was found to have good correlation with the parasite-based system. The 50% inhibitory concentrations derived from PvDHFR-TS-dependent bacteria were correlated with their corresponding inhibition constants (Ki ) from an enzyme inhibition assay, pointing to the likelihood that the potent enzyme inhibitors will also have potent antimalarial activities. Active compounds against both wild-type and S58R S117N (SP21) double-mutant P. vivax include analogs with structures which can avert a steric clash with the asparagine (S117N) side chain of the mutant, similar to those found for homologous Plasmodium falciparum mutants, raising the possibility that the same compounds can be developed against both types of antifolate-resistant malaria. This rapid and convenient drug screening system should be useful for development of new antifolates against P. vivax, for which a continuous culture system is not yet available.

scholarly journals Steep Rebound of Chloroquine-Sensitive Plasmodium falciparum in Zimbabwe

2020 ◽  
Author(s):  
Sungano Mharakurwa ◽  
Zvifadzo Matsena-Zingoni ◽  
Nobert Mudare ◽  
Charmaine Matimba ◽  
Tanatswa Xuxa Gara ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Drug Policy ◽  
Sub Saharan Africa ◽  
Wild Type ◽  
Control Programs ◽  
Antimalarial Resistance ◽  
Steep Decline ◽  
Vital Component ◽  
Sub Saharan

Abstract Removal of chloroquine from national malaria formularies can lead to the reversion of resistant Plasmodium falciparum to wild-type. We report a steep decline in chloroquine-resistant P falciparum within 10 years of national discontinuation of chloroquine monotherapy in Zimbabwe. Drug resistance surveillance is a vital component of malaria control programs, and the experience with chloroquine in Zimbabwe and elsewhere in sub-Saharan Africa is illustrative of the potentially rapid and dramatic impact of drug policy on antimalarial resistance.

scholarly journals Towards an Understanding of the Mechanism of Pyrimethamine-Sulfadoxine Resistance in Plasmodium falciparum: Genotyping of Dihydrofolate Reductase and Dihydropteroate Synthase of Kenyan Parasites

2000 ◽  
Vol 44 (4) ◽  
pp. 991-996 ◽  
Author(s):  
A. M. Nzila ◽  
E. K. Mberu ◽  
J. Sulo ◽  
H. Dayo ◽  
P. A. Winstanley ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Dihydrofolate Reductase ◽  
Double Mutant ◽  
Drug Resistant ◽  
Wild Type ◽  
Triple Mutant ◽  
Dihydropteroate Synthase ◽  
Before And After ◽  
Kenyan Coast ◽  
Wide Scale

ABSTRACT The antifolate combination of pyrimethamine (PM) and sulfadoxine (SD) is the last affordable drug combination available for wide-scale treatment of falciparum malaria in Africa. Wherever this combination has been used, drug-resistant parasites have been selected rapidly. A study of PM-SD effectiveness carried out between 1997 and 1999 at Kilifi on the Kenyan coast has shown the emergence of RI and RII resistance to PM-SD (residual parasitemia 7 days after treatment) in 39 out of 240 (16.25%) patients. To understand the mechanism that underlies resistance to PM-SD, we have analyzed the dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genotypes of 81 patients. Fifty-one samples were obtained, before treatment, from patients who remained parasite free for at least 7 days after treatment. For a further 20 patients, samples were obtained before treatment and again when they returned to the clinic with parasites 7 days after PM-SD treatment. Ten additional isolates were obtained from patients who were parasitemic 7 days after treatment but who were not sampled before treatment. More than 65% of the isolates (30 of 46) in the initial group had wild-type or double mutant DHFR alleles, and all but 7 of the 47 (85%) had wild-type DHPS alleles. In the paired (before and after treatment) samples, the predominant combinations of DHFR and DHPS alleles before treatment were of triple mutant DHFR and double mutant DHPS (41% [7 of 17]) and of double mutant DHFR and double mutant DHPS (29% [5 of 17]). All except one of the posttreatment isolates had triple mutations in DHFR, and most of these were “pure” triple mutants. In these isolates, the combination of a triple mutant DHFR and wild-type DHPS was detected in 6 of 29 cases (20.7%), the combination of a triple mutant DHFR and a single mutant (A437G) DHPS was detected in 4 of 29 cases (13.8%), and the combination of a triple mutant DHFR and a double mutant (A437G, L540E) DHPS was detected in 16 of 29 cases (55.2%). These results demonstrate that the triply mutated allele of DHFR with or without mutant DHPS alleles is associated with RI and RII resistance to PM-SD. The prevalence of the triple mutant DHFR-double mutant DHPS combination may be an operationally useful marker for predicting the effectiveness of PM-SD as a new malaria treatment.

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