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Query: UMLS:C0024530 (malaria)
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The malaria parasite contains a nuclear genome with 14 chromosomes and two extrachromosomal DNA molecules of 6 kb and 35 kb in size. The smallest genome, known as the 6 kb element or mitochondrial DNA, has been sequenced from several Plasmodium falciparum isolates because this is a potential drug target. Here we describe the complete nucleotide sequence of this element from an Indian isolate of P. falciparum. It is 5967 bp in size and shows 99.6% homology with the 6 kb element of other isolates. The element contains three open reading frames for mitochondrial proteins-cytochrome oxidase subunit I (CoI), subunit III (CoIII) and cytochrome b (Cyb) which were found to be expressed during blood stages of the parasite. We have also sequenced the entire cyb gene from several Indian isolates of P. falciparum. The rate of mutation in this gene was very low since 12 of 14 isolates showed the identical sequence. Only one isolate showed a maximum change in five amino acids whereas the other isolate showed only one amino acid change. However, none of the Indian isolates showed any change in those amino acids of cyb which are associated with resistance to various drugs as these drugs are not yet commonly used in India.
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PMID:Complete nucleotide sequence of the 6 kb element and conserved cytochrome b gene sequences among Indian isolates of Plasmodium falciparum. 1142 75

We report the first in vitro and genetic confirmation of Malarone (GlaxoSmithKline; atovaquone and proguanil hydrochloride) resistance in Plasmodium falciparum acquired in Africa. On presenting with malaria two weeks after returning from a 4-week visit to Lagos, Nigeria without prophylaxis, a male patient was given a standard 3-day treatment course of Malarone. Twenty-eight days later the parasitaemia recrudesced. Parasites were cultured from the blood and the isolate (NGATV01) was shown to be resistant to atovaquone and the antifolate pyrimethamine. The cytochrome b gene of isolate NGATV01 showed a single mutation, Tyr268Asn which has not been seen previously.
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PMID:Malarone treatment failure and in vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos, Nigeria. 1205 21

Drug resistance in malarial parasites has become a major obstacle in the control of the disease. Strategies are urgently needed to control the development of resistance and to possibly reverse existing resistance. One key element required to reverse malaria drug resistance is for the parasites to "pay" a biological "cost" or suffer a loss of fitness when acquiring resistance to antimalarial drugs. Such a situation would be a disadvantage to the resistant parasites in the absence of drug pressure. We compared here the relative fitness of atovaquone-resistant Plasmodium falciparum K1 clones with single and double base mutations in their cytochrome b genes to their parent clones during erythrocytic stages in the absence of drug pressure. We found that the double amino acid mutation (M133I and G280D) is associated with a 5 to 9% loss of fitness and that the single amino acid change of M133I did not result in any detectable loss of fitness. Molecular modeling of the interaction of P. falciparum cytochrome b with ubiquinone led to the prediction that a loss of fitness of the malaria parasites would result from the G280D mutation due to its close proximity to the putative ubiquinone-binding site. This appears to have resulted in a weakening of the cytochrome b-ubiquinone complex, thereby causing the electron transport chain to become less efficient. Our results suggest that the prevalence of resistant parasites may decrease after the drug usage is discontinued.
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PMID:Mutations in cytochrome b resulting in atovaquone resistance are associated with loss of fitness in Plasmodium falciparum. 1212 15

Here, 4 polymerase chain reaction (PCR) assays are compared to test for the presence of avian malaria, including both the Plasmodium and Haemoproteus genera, in 29 different species of African rainforest birds. Two of these PCR assays use primer sets that amplify fragments of the cytochrome b (cyt b) gene of Plasmodium; the other 2 target the 18S ribosomal subunit gene. These PCR assays were performed using genomic DNA extracted from blood and subsequently compared with the results obtained by microscopic examination of blood smears taken from the same individuals. The 2 primer sets amplifying the cyt b gene were found to perform more reliably than those that target the 18S rRNA gene and yielded a substantial number of positive samples that were undetected by blood smear analysis. Of all the individuals screened by PCR, 40% tested positive for avian malaria, whereas 27% tested positive by blood smear analysis. Although sequence variation in the parasites may prohibit the specific alignment of primers and the subsequent PCR amplification of some individuals, PCR, once optimized, is faster, cheaper, and more reliable than blood smear analysis for large-scale screening.
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PMID:A comparative analysis of PCR-based detection methods for avaian malaria. 1219 45

Clinical treatment failures of the hydroxynaphthoquinone atovaquone or its combination with proguanil (Malarone) in Plasmodium falciparum malaria has been recently documented. These events have been associated to single nucleotide polymorphisms (SNPs) in the parasite cytochrome b gene (cytb). In this report we describe a set of nest PCR-RFLP methods developed for the fast detection of all known cytb mutations associated to resistance to these drugs. The methods were successfully applied for the analysis of phenol-chloroform extracted DNA samples from patients not cured by Malarone, and from an established parasite clone. Further, the protocol for the detection of the A803C mutation was applied to 164 DNA field samples extracted through crude methanol-based protocols, originated from several malaria settings. The PCR-RFLP methods here presented can be used as a valuable for the clinical detection and study of Malarone and atovaquone P. falciparum resistance.
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PMID:Detection of atovaquone and Malarone resistance conferring mutations in Plasmodium falciparum cytochrome b gene (cytb). 1278 29

Atovaquone is a substituted hydroxynaphthoquinone that is widely used to prevent and clear Plasmodium falciparum malaria and Pneumocystis jirovecii pneumonia. Atovaquone inhibits respiration in target organisms by specifically binding to the ubiquinol oxidation site at center P of the cytochrome bc(1) complex. The failure of atovaquone treatment and mortality of patients with malaria and P. jirovecii pneumonia has been linked to the appearance of mutations in the cytochrome b gene. To better understand the molecular basis of atovaquone resistance, we have introduced seven of the mutations from atovaquone-resistant P. jirovecii into the cytochrome b gene of Saccharomyces cerevisiae and thus obtained cytochrome bc(1) complexes resistant to inhibition by atovaquone. In these enzymes, the IC(50) for atovaquone increases from 25 nm for the enzyme from wild-type yeast to >500 nm for some of the mutated enzymes. Modeling of the changes in cytochrome b structure and atovaquone binding with the mutated bc(1) complexes provides the first quantitative explanation for the molecular basis of atovaquone resistance.
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PMID:Molecular basis for atovaquone resistance in Pneumocystis jirovecii modeled in the cytochrome bc(1) complex of Saccharomyces cerevisiae. 1457 56

Many malaria control programmes are based on insecticide application as adulticides, often in the form of pyrethroid-impregnated bed nets. However, the efficacy of this control measure can be reduced by genetic changes in vector insecticide susceptibility. Pyrethroid resistance has been detected in the major African malaria vector, Anopheles gambiae, and has been attributed to a combination of target site insensitivity and increased oxidative metabolism of the insecticide, catalysed by cytochrome P450s. An adult-specific cytochrome P450 monooxygenase 6 (CYP6) P450 gene, CYP6Z1, located within a large cluster of cytochrome P450 genes in chromosome arm 3R of An. gambiae, is expressed approximately 11-fold higher in males and 4.5-fold in females from a pyrethroid-resistant strain than in a susceptible strain from the same geographical area. In both strains, CYP6Z1 expression is higher in males than females. Southern blot analysis discounted gene amplification as a cause of this overexpression. The isolation of An. gambiae cDNAs encoding cytochrome b(5) and nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH)-cytochrome P450 reductase cDNAs is also reported.
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PMID:An adult-specific CYP6 P450 gene is overexpressed in a pyrethroid-resistant strain of the malaria vector, Anopheles gambiae. 1458 2

Seven of 28 passerine birds that died in captivity were positive for malarial parasites by polymerase chain reaction targeting the mitochondrial cytochrome b (cytB) and apicoplast ribosomal RNA (rRNA) genes. Each bird was infected with a single parasite lineage having a unique genotype. Apicoplast rRNA sequences were present both in Haemoproteus spp. and Plasmodium spp. and had typically high adenosine + thymidine content. Phylogenies for cytB and apicoplast rRNA sequences were largely congruent and supported previous studies that suggest that Plasmodium-Haemoproteus spp. underwent synchronous speciation with their avian hosts, interrupted by sporadic episodes of host switching. Apicoplast phylogeny further indicated that Haemoproteus spp. are ancestral to Plasmodium spp. All the 7 infected passerine birds had histologic lesions of malaria, and malarial parasites may have contributed to the death of at least 4 animals. These findings provide new genetic data on passerine hematozoa, including initial sequences of apicoplast DNA, and emphasize the relevance of parasite prevalence, evolutionary relationships, and host switching to modern management and husbandry practices of captive birds.
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PMID:Molecular characterization of malarial parasites in captive passerine birds. 1462 51

We used phylogenetic analyses of cytochrome b sequences of malaria parasites and their avian hosts to assess the coevolutionary relationships between host and parasite lineages. Many lineages of avian malaria parasites have broad host distributions, which tend to obscure cospeciation events. The hosts of a single parasite or of closely related parasites were nonetheless most frequently recovered from members of the same host taxonomic family, more so than expected by chance. However, global assessments of the relationship between parasite and host phylogenetic trees, using Component and ParaFit, failed to detect significant cospeciation. The event-based approach employed by TreeFitter revealed significant cospeciation and duplication with certain cost assignments for these events, but host switching was consistently more prominent in matching the parasite tree to the host tree. The absence of a global cospeciation signal despite conservative host distribution most likely reflects relatively frequent acquisition of new hosts by individual parasite lineages. Understanding these processes will require a more refined species concept for malaria parasites and more extensive sampling of parasite distributions across hosts. If parasites can disperse between allopatric host populations through alternative hosts, cospeciation may not have a strong influence on the architecture of host-parasite relationships. Rather, parasite speciation may happen more often in conjunction with the acquisition of new hosts followed by divergent selection between host lineages in sympatry. Detailed studies of the phylogeographic distributions of hosts and parasites are needed to characterize these events.
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PMID:Evolutionary relationships, cospeciation, and host switching in avian malaria parasites. 1496 6

Atovaquone-proguanil has recently been introduced for the treatment and prophylaxis of malaria. However, resistance of Plasmodium falciparum is increasingly reported. We assessed P. falciparum polymorphisms associated with resistance to atovaquone (cytochrome b, cytb) and to cycloguanil, the active compound of proguanil (dihydrofolate reductase, dhfr) in 100 isolates from northern Ghana. None of these exhibited cytb codon 268 mutations. Moreover, no dhfr V16A, S108T or I164L mutations linked with cycloguanil resistance were detected. However, dhfr triple mutants (S108N-I51L-C59R) conferring resistance to proguanil and sulphadoxine-pyrimethamine were seen in 51% of the isolates. In northern Ghana, P. falciparum cytb codon 268 mutations associated with atovaquone resistance are absent. Although proguanil appears to act synergistically with atovaquone in a way different from its antifolate property, the abundance of dhfr polymorphisms will likely compromise the prevention of dissemination of atovaquone-resistant parasites once emerged.
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PMID:Short communication: Prevalence of mutations associated with resistance to atovaquone and to the antifolate effect of proguanil in Plasmodium falciparum isolates from northern Ghana. 1499 65


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