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)

Anopheles sundaicus s.l. is a principal malaria vector taxon on islands and along the coastal areas of Southeast Asia. It has a wide geographical distribution and exhibits a high level of ecological and behavioral variability. Study of this taxon is crucial for understanding its biology and implementing effectise vector control measures. We compared populations of An. sundaicus from Vietnam, Thailand, and Malaysian Borneo by using two mitochondrial DNA markers: cytochrome oxidase I and cytochrome b. Genetic divergence, geographic separation, and cladistic analysis of relationships revealed the presence of two cryptic species: Anopheles sundaicus s.s. on Malaysian Borneo and An. sundaicus species A in coastal areas of Thailand and Vietnam. A polymerase chain reaction (PCR) assay was developed to easily identify these two species throughout their geographic distributions. The assay was based on sequence characterized amplified region derived from random amplified polymorphic DNA. This PCR identification method needs to be validated and adapted for the recognition of other possible species in the Sundaicus Complex.
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PMID:Molecular evidence of speciation between island and continental populations of Anopheles (Cellia) sundaicus (Diptera: Culicidae), a principal malaria vector taxon in Southeast Asia. 1518 27

Malarone (atovaquone-proguanil) is an effective drug for the treatment and prophylaxis of multidrug-resistant falciparum malaria. However, first cases of resistance have been reported, which are associated with mutations at codon 268 of the parasite's cytochrome b gene. We report the first case of Malarone treatment failure from Central Africa.Drug concentration was well within curative range. Pre- and post-treatment Plasmodium falciparum isolates revealed codon 268 wild-type alleles, and no other mutations of the putative atovaquone-binding domain.These findings illustrate the spread of atovaquone-proguanil-resistance in Africa and question the usefulness of codon 268 as the only target for the surveillance of its emergence.
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PMID:Malarone treatment failure not associated with previously described mutations in the cytochrome b gene. 1518 99

Analyses of mitochondrial cytochrome b diversity among avian blood parasites of the genera Haemoproteus and Plasmodium suggest that there might be as many lineages of parasites as there are species of birds. This is in sharp contrast to the approximately 175 parasite species described by traditional methods based on morphology using light microscopy. Until now it has not been clear to what extent parasite mitochondrial DNA lineage diversity reflects intra- or interspecific variation. We have sequenced part of a fast-evolving nuclear gene, dihydrofolate reductase-thymidylate synthase (DHFR-TS), and demonstrate that most of the parasite mitochondrial DNA lineages are associated with unique gene copies at this locus. Although these parasite lineages sometimes coexist in the same host individual, they apparently do not recombine and could therefore be considered as functionally distinct evolutionary entities, with independent evolutionary potential. Studies examining parasite virulence and host immune systems must consider this remarkable diversity of avian malaria parasites.
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PMID:Linkage between nuclear and mitochondrial DNA sequences in avian malaria parasites: multiple cases of cryptic speciation? 1534 Nov 64

We describe a case of naturally acquired infection with Plasmodium knowlesi in Thailand. Diagnosis was confirmed by the small subunit ribosomal RNA and the mitochondrial cytochrome b sequences. The occurrence of simian malaria in human has signified the roles of wild primate populations in disease transmission in some malaria-endemic areas.
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PMID:Naturally acquired Plasmodium knowlesi malaria in human, Thailand. 1566 64

Atovaquone is a new anti-malarial agent that specifically targets the cytochrome bc1 complex and inhibits parasite respiration. A growing number of failures of this drug in the treatment of malaria have been genetically linked to point mutations in the mitochondrial cytochrome b gene. To better understand the molecular basis of atovaquone resistance in malaria, we introduced five of these mutations, including the most prevalent variant found in Plasmodium falciparum (Y268S), into the cytochrome b gene of the budding yeast Saccharomyces cerevisiae and thus obtained cytochrome bc1 complexes resistant to inhibition by atovaquone. By modeling the variations in cytochrome b structure and atovaquone binding with the mutated bc1 complexes, we obtained the first quantitative explanation for the molecular basis of atovaquone resistance in malaria parasites.
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PMID:Cytochrome b mutations that modify the ubiquinol-binding pocket of the cytochrome bc1 complex and confer anti-malarial drug resistance in Saccharomyces cerevisiae. 1571 26

We recovered 26 genetically distinct avian malaria parasite lineages, based on cytochrome b sequences, from a broad survey of terrestrial avifauna of the Lesser Antilles. Here we describe their distributions across host species within a regional biogeographic context. Most parasite lineages were recovered from a few closely related host species. Specialization on one host species and distribution across many hosts were both rare. Geographic patterns of parasite lineages indicated limited dispersal and frequent local extinction. The central islands of the archipelago share similar parasite lineages and patterns of infection. However, the peripheral islands harbor well-differentiated parasite communities, indicating long periods of isolation. Nonetheless, 20 of 26 parasite lineages were recovered from at least one of three other geographic regions, the Greater Antilles, North America, and South America, suggesting rapid dispersal relative to rate of differentiation. Six parasite lineages were restricted to the Lesser Antilles, primarily to endemic host species. Host differences between populations of the same parasite lineage suggest that host preference may evolve more rapidly than mitochondrial gene sequences. Taken together, distributions of avian malarial parasites reveal evidence of coevolution, host switching, extinction, and periodic recolonization events resulting in ecologically dynamic as well as evolutionarily stable patterns of infection.
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PMID:Host specialization and geographic localization of avian malaria parasites: a regional analysis in the Lesser Antilles. 1579 38

The DNA sequence information on avian malaria parasites of the genus Plasmodium is quite limited. At present, sequences of only 6 out of 34 valid species are available. However, sequence data of avian malaria parasites are particularly important with regard to the resolution of the phylogenetic relationships of the most virulent human malaria agent, Plasmodium falciparum. The question as to whether P. falciparum originates from avian or from mammalian parasites would contribute to our understanding of its biology and would probably facilitate the interpretation of experimental results. To add to the body of molecular data, we sequenced three genes (cytochrome b, 18 SSU rRNA, caseinolytic protease C) of different organellar origin of one of the most widespread avian malaria parasites, Plasmodium (Haemamoeba) cathemerium, which once used to be an important laboratory in vivo model in human malaria research. The analysis of the new P. cathemerium sequences in direct comparison with the rodent parasite P. berghei and the four human malaria parasites by pairwise distance calculation do not suggest a closer relationship of P. cathemerium to P. falciparum than to the other species involved.
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PMID:Plasmodium (Haemamoeba) cathemerium gene sequences for phylogenetic analysis of malaria parasites. 1581 72

The importation of drug-resistant malaria is a growing public health problem in non-endemic countries. The combination of atovaquone and proguanil (Malarone) has become established as an agent of choice to prevent and treat chloroquine-resistant Plasmodium falciparum malaria in travelers. We describe the first reported case in North America of genetically confirmed atovaquone/proguanil-resistant P. falciparum malaria. Polymerase chain reaction and sequence analysis of the primary and recrudescent isolates confirmed the acquisition of a point mutation (Tyr268Ser) in the cytochrome b gene of the recrudescent isolate known to confer high-level resistance to atovaquone. Suboptimal therapy may have played a contributory role in the emergence of resistance.
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PMID:Emergence of atovaquone-proguanil resistance during treatment of Plasmodium falciparum malaria acquired by a non-immune north American traveller to west Africa. 1582 76

Cytochrome b from yeast (Saccharomyces cerevisiae Meyer ex Hansen) provides a convenient model system for the study of Qo-site inhibitor (QoI) resistance mutations from a variety of organisms. QoI resistance mutations from fungal plant pathogens (G143A and F129L), malaria agent Plasmodium sp (Y279C/S), and Pneumocystis carinii (L275F), an opportunistic pathogenic fungus of man, were introduced into yeast cytochrome b and their effect on the binding of a variety of natural (myxothiazol and stigmatellin) and synthetic (atovaquone, azoxystrobin and pyraclostrobin) inhibitors to the bc1 complex monitored. L275S (from a myxothiazol-resistant yeast) was also re-examined. Stigmatellin binding was relatively unaffected by the introduction of these mutations. Significant increases in resistance were observed for the strobilurin-class inhibitors myxothiazol, azoxystrobin and pyraclostrobin, with the largest increase in resistance conferred by G143A. In contrast, atovaquone binding was most effected by Y279C/S and L275S. Notably, F129L, G143A and L275S had a minor effect on bc1 activity, and so are unlikely to confer significant fitness penalties in vivo. These data are discussed in the light of the atomic structures for myxothiazol- and azoxystrobin-inhibited bovine bc1 which have recently become available. We propose that QoI resistance due to G143A arises from steric hindrance between the inhibitor and cytochrome b, whereas the mechanism of resistance for the other mutations is due to an increase in binding energy between the protein and inhibitor molecule. Site-directed mutagenesis was also used to model selected regions of the mammalian Qo site in yeast cytochrome b in order to further understand the differential efficacy of these QoI in the mammalian and pathogen bc1 complexes.
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PMID:Re-examination of inhibitor resistance conferred by Qo-site mutations in cytochrome b using yeast as a model system. 1591 60

Atovaquone is an antiparasitic drug that selectively inhibits electron transport through the parasite mitochondrial cytochrome bc1 complex and collapses the mitochondrial membrane potential at concentrations far lower than those at which the mammalian system is affected. Because this molecule represents a new class of antimicrobial agents, we seek a deeper understanding of its mode of action. To that end, we employed site-directed mutagenesis of a bacterial cytochrome b, combined with biophysical and biochemical measurements. A large scale domain movement involving the iron-sulfur protein subunit is required for electron transfer from cytochrome b-bound ubihydroquinone to cytochrome c1 of the cytochrome bc1 complex. Here, we show that atovaquone blocks this domain movement by locking the iron-sulfur subunit in its cytochrome b-binding conformation. Based on our malaria atovaquone resistance data, a series of cytochrome b mutants was produced that were predicted to have either enhanced or reduced sensitivity to atovaquone. Mutations altering the bacterial cytochrome b at its ef loop to more closely resemble Plasmodium cytochrome b increased the sensitivity of the cytochrome bc1 complex to atovaquone. A mutation within the ef loop that is associated with resistant malaria parasites rendered the complex resistant to atovaquone, thereby providing direct proof that the mutation causes atovaquone resistance. This mutation resulted in a 10-fold reduction in the in vitro activity of the cytochrome bc1 complex, suggesting that it may exert a cost on efficiency of the cytochrome bc1 complex.
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PMID:Uncovering the molecular mode of action of the antimalarial drug atovaquone using a bacterial system. 1591 36


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