Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monitoring changes in the frequencies of drug-resistant and -sensitive genotypes can facilitate in vivo clinical trials to assess the efficacy of drugs before complete failure occurs. Peru changed its national treatment policy for uncomplicated malaria to artesunate (ART)-plus-mefloquine (MQ) combination therapy in the Amazon basin in 2001. We genotyped isolates collected in 1999 and isolates collected in 2006 to 2007 for mutations in the Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes, multidrug resistance gene 1 (Pfmdr-1), the chloroquine (CQ) resistance transporter gene (Pfcrt), and the Ca(2+) ATPase gene (PfATP6); these have been shown to be involved in resistance to sulfadoxine-pyrimethamine (SP), MQ, CQ, and possibly ART, respectively. Microsatellite haplotypes around the Pfdhfr, Pfdhps, Pfcrt, and Pfmdr-1 loci were also determined. There was a significant decline in the highly SP resistant Pfdhfr and Pfdhps genotypes from 1999 to 2006. In contrast, a CQ-resistant Pfcrt genotype increased in frequency during the same period. Among five different Pfmdr-1 allelic forms noted in 1999, two genotypes increased in frequency while one genotype decreased by 2006. We also noted previously undescribed polymorphisms in the PfATP6 gene as well as an increase in the frequency of a deletion mutant during this period. In addition, microsatellite analysis revealed that the resistant Pfdhfr, Pfdhps, and Pfcrt genotypes have each evolved from a single founder haplotype, while Pfmdr-1 genotypes have evolved from at least two independent haplotypes. Importantly, this study demonstrates that the Peruvian triple mutant Pfdhps genotypes are very similar to those found in other parts of South America.
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PMID:Dynamics of malaria drug resistance patterns in the Amazon basin region following changes in Peruvian national treatment policy for uncomplicated malaria. 2040 29

Point mutations in the dhfr and dhps genes of Plasmodium falciparum are associated with pyrimethamine and sulfadoxine resistance respectively. In this study we have analyzed these genes from Bikaner (situated in North-West region of India), where both uncomplicated and severe manifestations of P. falciparum malaria are seen. A majority of isolates showed double mutant allele for DHFR. In contrast, the only reported mutation present in DHPS was A437G in few isolates. In addition, three novel non-synonymous mutations were observed in the PfDHPS from this region viz., S587F, N666K and C668W. The mutations at the 666 and 668 codon seem to form a bend in the big loop region of the DHPS enzyme and may affect the binding of the drug to the enzyme. Molecular docking of sulfadoxine to this mutated structure indicates reduction in its binding affinity to this enzyme.
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PMID:Novel point mutations in sulfadoxine resistance genes of Plasmodium falciparum from India. 1928 99

In January 2007, Tanzania replaced sulfadoxine-pyrimethamine (SP) with artemether-lumefantrine for treatment of uncomplicated malaria. This study examined the impact of widespread SP use on molecular markers of Plasmodium falciparum drug resistance in blood samples from persons living in two villages in Korogwe District, Tanzania, from 2003 through 2007. The prevalence of the P. falciparum dihydropteroate synthase (Pfdhps) gene 581G mutation increased from 12% in 2003 to 56% in 2007 (P < 0.001), resulting in an increase in the triple mutant Pfdhps haplotype SGEGA from 8% to 32% (P < 0.001). In contrast, the chloroquine-sensitive P. falciparum chloroquine resistance transporter (Pfcrt) CVMNK haplotype increased from 6% to 30% (P < 0.001). The dramatic increase of the triple Pfdhps mutant SGEGA haplotype may endanger the continued use of SP for intermittent presumptive treatment of pregnant women (IPTp). Further studies are needed to determine the importance of Pfdhps SGEGA haplotype parasites on the efficacy of SP for IPTp.
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PMID:Five-year surveillance of molecular markers of Plasmodium falciparum antimalarial drug resistance in Korogwe District, Tanzania: accumulation of the 581G mutation in the P. falciparum dihydropteroate synthase gene. 1934 69

Typing of polymorphic microsatellites that are linked to drug resistance genes has shed light on the origin and pattern of spread of some anti-malarial drugs. Recent surveys revealed spread of a high-level pyrimethemine resistant lineage of Plasmodium falciparum, of Asian origin, across Africa. Here, we examined mutations in dihydrofolate reductase, dhfr [chromsosome 4], the dihydropteroate synthase, dhps [chromosome 8] associated with resistance to sulfadoxine-pyrimethamine (SP), and neighboring microsatellites among P. falciparum isolates in Asar village, eastern Sudan. This area lies at the fringes of malaria endemicity, where the remote P. falciparum parasites have some distinct genetic characteristics. Overall, 89% (84/94) of the examined isolates carried double mutations at dhfr (N51I and S108N), but the 59R and I164L mutations were not seen. Similarly, the majority, 43% (35/81) of the isolates carried double mutations at dhps (437G, 540E). Analysis of neighboring microsatellites revealed one major dhfr haplotype with mutations (51I, 108N) and one dhps haplotype with mutations (436S, 437G, 540E). These haplotypes differ from the major ones thought to drive resistance to SP across Africa. The resistant haplotypes of dhfr and dhps, in Asar, share some microsatellites with the wild genotypes suggesting that they were generated locally. Among isolates successfully examined, 40% shared identical haplotypes of the 2 loci, comprising a dominant resistant lineage. Undoubtedly, this lineage plays an important role in clinical failure to SP in this area.
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PMID:Distinct haplotypes of dhfr and dhps among Plasmodium falciparum isolates in an area of high level of sulfadoxine-pyrimethamine (SP) resistance in eastern Sudan. 1937 43

Intermittent preventive treatment in pregnancy (IPTp) is used to prevent Plasmodium falciparum malaria. However, parasites resistant to the IPTp drug sulfadoxine-pyrimethamine (SP) have emerged worldwide, and infections with mixed resistant and susceptible parasites are exacerbated by pyrimethamine in mice. In a prospective delivery cohort in Muheza, Tanzania, we examined the effects of SP IPTp on parasite resistance alleles, parasite diversity, level of parasitemia, and inflammation in the placenta. IPTp use was associated with an increased fraction of parasites carrying the resistance allele at DHPS codon 581, an increase in the level of parasitemia, and more intense placental inflammation. The lowest mean level of parasite diversity and highest mean level of parasitemia occurred in women after recent IPTp use. These findings support a model of parasite release and facilitation, whereby the most highly resistant parasites out-compete less fit parasite populations and overgrow under drug pressure. Use of partially effective anti-malarial agents for IPTp may exacerbate malaria infections in the setting of widespread drug resistance.
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PMID:Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment. 1945 38

Plasmodium vivax isolates from French Guiana were studied for the presence of mutations associated with sulfadoxine/pyrimethamine (SP) drug resistance. Ninety-six blood samples were collected from 2000 to 2005 from symptomatic malaria patients. SP drug resistance was predicted by determining point mutations in the dihydrofolate reductase (pvdhfr) and dihydropteroate synthase (pvdhps) genes. All samples showed mutant genotypes in both genes with a prevalence > 90% for the 58R, 117N, 382C, and 383G. A new mutation (116G) in pvdhfr was found at a frequency of 3.3%. Six different pvdhfr/dhps multilocus genotypes were observed with the predominance of the quintuple mutant-type 58R/117N/173L-382C/383G (59.3%). No significant differences were observed between the prevalence of haplotypes and the year of collection. Our results indicate that, in this area, the fixation of SP drug-resistant parasites in the P. vivax population is stable.
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PMID:High prevalence and fixation of Plasmodium vivax dhfr/dhps mutations related to sulfadoxine/pyrimethamine resistance in French Guiana. 1955 60

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.
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PMID:Characteristics of genetic hitchhiking around dihydrofolate reductase gene associated with pyrimethamine resistance in Plasmodium falciparum isolates from India. 1978 3

Antifolate drugs have an important role in the treatment of malaria. Polymorphisms in the genes encoding the dihydrofolate reductase and dihydropteroate synthetase enzymes cause resistance to the antifol and sulfa drugs, respectively. Rwanda has the highest levels of antimalarial drug resistance in Africa. We correlated the efficacy of chlorproguanil-dapsone plus artesunate (CPG-DDS+A) and amodiaquine plus sulfadoxine-pyrimethamine (AQ+SP) in children with uncomplicated malaria caused by Plasmodium falciparum parasites with pfdhfr and pfdhps mutations, which are known to confer reduced drug susceptibility, in two areas of Rwanda. In the eastern province, where the cure rates were low, over 75% of isolates had three or more pfdhfr mutations and two or three pfdhps mutations and 11% had the pfdhfr 164-Leu polymorphism. In the western province, where the cure rates were significantly higher (P < 0.001), the prevalence of multiple resistance mutations was lower and the pfdhfr I164L polymorphism was not found. The risk of treatment failure following the administration of AQ+SP more than doubled for each additional pfdhfr resistance mutation (odds ratio [OR] = 2.4; 95% confidence interval [CI] = 1.01 to 5.55; P = 0.048) and each pfdhps mutation (OR = 2.1; 95% CI = 1.21 to 3.54; P = 0.008). The risk of failure following CPG-DDS+A treatment was 2.2 times higher (95% CI = 1.34 to 3.7) for each additional pfdhfr mutation, whereas there was no association with mutations in the pfdhps gene (P = 0.13). The pfdhfr 164-Leu polymorphism is prevalent in eastern Rwanda. Antimalarial treatments with currently available antifol-sulfa combinations are no longer effective in Rwanda because of high-level resistance.
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PMID:Molecular correlates of high-level antifolate resistance in Rwandan children with Plasmodium falciparum malaria. 1984 Nov 50

Plasmodium falciparum is the main cause of human malaria and is one of the important pathogens causing high rates of morbidity and mortality. The total number of malaria patients in Vietnam has gradually decreased over the last decade. However, the spread of pathogens with drug resistance remains a significant problem. Defining the trend in genotypes related to drug resistance is essential for the control of malaria in Vietnam. We undertook a longitudinal survey of Plasmodium falciparum malaria in 2001, 2002, and 2005 to 2007. The pfcrt, pfmdr1, pfdhfr, and pfdhps genes were analyzed by sequencing; and correlations by study year, age, gender, and genotype were identified statistically. The ratio of the chloroquine resistance genotype pfcrt 76T was found to have decreased rapidly after 2002. High numbers of mutations in the pfdhfr and pfdhps genes were observed only in 2001 and 2002, while the emergence of parasites with a new K540Y mutation in the P. falciparum dihydropteroate synthetase (PfDHPS) was observed in 2002. For males and those in younger age brackets, a correlation between vulnerability to P. falciparum infection and strains with pfcrt 76K or strains with decreased numbers of mutations in pfdhfr and pfdhps was demonstrated. The parasites with pfcrt 76T exhibited a greater number of mutations in pfdhfr and pfdhps.
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PMID:Longitudinal survey of Plasmodium falciparum infection in Vietnam: characteristics of antimalarial resistance and their associated factors. 1988 91

Accumulation of mutations in dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) is strongly associated with sulfadoxine-pyrimethamine (SP) treatment failure. Routine surveillance for these resistance markers was conducted annually at 26 sentinel sites in Maputo Province, Mozambique, before and after the phased deployment of artesunate plus SP (AS-SP), with 15,758 children sampled between 2004 and 2008. Mean asexual parasite prevalence, polymerase chain reaction (PCR) corrected, decreased from 44.2% in 2004 to 3.8% in 2008 (P < 0.0001). Among the 2,012 PCR-confirmed falciparum samples, the dhfr triple mutation remained close to fixation, whereas both dhps double and dhfr/dhps "quintuple" mutations increased from 11.0% in 2004, to 75.0% by 2008 (P < 0.0001). Adding artesunate to SP did not retard the spread of SP-resistant parasites. The high "quintuple" mutation prevalence suggests a limited useful therapeutic lifespan of AS-SP for treating uncomplicated malaria, and may curb efficacy of SP-monotherapy for intermittent preventive treatment in Mozambique.
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PMID:Five years of large-scale dhfr and dhps mutation surveillance following the phased implementation of artesunate plus sulfadoxine-pyrimethamine in Maputo Province, Southern Mozambique. 2043 56


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