Download or read book Molecular Characterization of Mefloquine Resistance in Plasmodium Falciparum written by and published by . This book was released on 1990 with total page 22 pages. Available in PDF, EPUB and Kindle. Book excerpt: The molecular basis for mefloquine resistance in the human malaria parasite, Plasmodium falciparum was investigated using recombinant DNA techniques. The parasites were found to be capable of manifesting extremely high levels of resistance to the drug in vitro. Resistant lines were found to be rapidly growing, impervious to various treatments, and significantly stimulated to grow by low levels of mefloquine. At the molecular levels, it was found that the genes for tubulin, a calmodulin-like protein, and a P-glycoprotein-like protein were all amplified in a quantitative relationship to the degree of resistance. Clones for each of these genes were isolated and characterized. Attempts were made to induce the amplification of tubulin genes in a sensitive parasite to see whether this event would confer resistance. High levels of vinblastine resistance were achieved but without evidence of gene amplification. Hence, the exact relationship between the amplification event and drug resistance remains unresolved. Keywords: Biotechnology; DNA structure; Drugs; Infectious diseases; Malaria; Mefloquine; Plasmodium; Parasitology.

Download or read book Molecular Characterisation of the Plasmodium Falciparum Pfcrt Gene Involved in Chloroquine Resistance written by and published by . This book was released on 2008 with total page 168 pages. Available in PDF, EPUB and Kindle. Book excerpt: Chloroquine (CQ) resistant P. falciparum was first reported in the 1960s at the Thai-Cambodia border. Gradually CQ resistance has spread and is found in all regions where P. falciparum transmission occurs. The emergence of CQ resistance due to excessive CQ selection pressure on the parasite populations has become an important issue because of the higher mortality and morbidity associated with drug resistance. Currently CQ is no longer recommended to treat falciparum malaria. CQ resistance in P. falciparum has been attributed to a single amino acid substitution on the P. falciparum chloroquine resistant transporter (pfcrt) at position 76 where Iysine is substituted with threonine (K76T). Molecular studies showed that CQ resistance emerged independently at five different geographical locations namely: Southeast Asia, two sites in South America, Papua New Guinea and the Philippines. Further analysis of resistant isolates revealed 22 additional non-silent amino acid substitutions on the pfcrt gene with a new amino acid substitution detected in the study reported here.

Download or read book Antimalarial Chemotherapy written by Philip J. Rosenthal and published by Springer Science & Business Media. This book was released on 2001-04-01 with total page 393 pages. Available in PDF, EPUB and Kindle. Book excerpt: Philip Rosenthal, MD, and a panel of leading malaria experts drawn from academia, the military, and international health organizations survey the latest scientific understanding of antimalarial chemotherapy, emphasizing the molecular mechanisms of resistance and the description of important new targets. Their survey covers the current status of malarial and antimalarial chemotherapy, the relevant biology and biochemistry of malaria parasites, the antimalarial drugs currently available, new chemical approaches to chemotherapy, and possible new targets for chemotherapy. Comprehensive and cutting-edge, Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and New Directions in Drug Discovery clearly delineates all the basic and clinical research now addressing one of the world's major unresolved disease problems, work that is now powerfully driving the rapid pace of antimalarial drug discovery today.

Download or read book Identification and Characterization of Novel Drug Resistance Loci in Plasmodium Falciparum written by Daria Natalie Van Tyne and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria has plagued mankind for millennia. Antimalarial drug use over the last century has generated highly drug-resistant parasites, which amplify the burden of this disease and pose a serious obstacle to control efforts. This dissertation is motivated by the simple fact that malaria parasites have become resistant to nearly every antimalarial drug that has ever been used, yet the precise genetic mechanisms of parasite drug resistance remain largely unknown. Our work pairs genomics-age technologies with molecular biology, genetics and molecular epidemiology in order to identify and characterize novel genes that contribute to drug resistance in P. falciparum.

Download or read book Antimalarial Drug Resistance in Southern Mozambique written by and published by . This book was released on 2004 with total page 152 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Analysis of the Cellular and Molecular Mechanisms of Chloroquine Resistance in Plasmodium Falciparum written by and published by . This book was released on 2009 with total page 296 pages. Available in PDF, EPUB and Kindle. Book excerpt: The CQR phenotype has traditionally been defined at low nanomolar cytostatic CQ concentrations but these do not correspond to medically relevant cytotoxic doseages. Thus, CQ accumulation was also measured using 3H-CQ and infected red blood cells at external CQ that corresponds to cytotoxic vs cytostatic concentrations. It was discovered that reduced CQ accumulation is not the underlying cause of cytotoxic CQR.

Download or read book Analysis of Plasmodium Falciparum Chloroquine Resistance Transporters in Saccharomyces Cerevisiae written by Nicholas Kyle Baro and published by . This book was released on 2012 with total page 492 pages. Available in PDF, EPUB and Kindle. Book excerpt: This study demonstrates the use of a model eukaryotic heterologous system to elucidate key features of a resistance protein from malaria parasites and highlights the potential of using this system to characterize its endogenous substrate.

Download or read book Saving Lives Buying Time written by Institute of Medicine and published by National Academies Press. This book was released on 2004-09-09 with total page 384 pages. Available in PDF, EPUB and Kindle. Book excerpt: For more than 50 years, low-cost antimalarial drugs silently saved millions of lives and cured billions of debilitating infections. Today, however, these drugs no longer work against the deadliest form of malaria that exists throughout the world. Malaria deaths in sub-Saharan Africaâ€"currently just over one million per yearâ€"are rising because of increased resistance to the old, inexpensive drugs. Although effective new drugs called "artemisinins" are available, they are unaffordable for the majority of the affected population, even at a cost of one dollar per course. Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance examines the history of malaria treatments, provides an overview of the current drug crisis, and offers recommendations on maximizing access to and effectiveness of antimalarial drugs. The book finds that most people in endemic countries will not have access to currently effective combination treatments, which should include an artemisinin, without financing from the global community. Without funding for effective treatment, malaria mortality could double over the next 10 to 20 years and transmission will intensify.

Download or read book P Falciparum and Its Molecular Markers of Resistance to Antimalarial Drugs written by Peter Hodoameda and published by . This book was released on 2019 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The use of molecular markers of resistance to monitor the emergence, and the spread of parasite resistance to antimalarial drugs is a very effective way of monitoring antimalarial drug resistance. The identification and validation of molecular markers have boosted our confidence in using these tools to monitor resistance. For example, P. falciparum chloroquine resistance transporter (PfCRT), P. falciparum multidrug resistance protein 1 (PfMDR1), P. falciparum multidrug kelch 13 (pfk13), have been identified as molecular markers of resistance to chloroquine, lumefantrine, and artemisinin respectively. The mechanism of resistance to antimalarial drugs is mostly by; (1) undergoing mutations in the parasite genome, leading to expelling the drug from the digestive vacuole, or (2) loss of binding affinity between the drug and its target. Increased copy number in the pfmdr1 gene also leads to resistance to antimalarial drugs. The major cause of the widespread chloroquine and sulfadoxine-pyrimethamine resistance globally is the spread of parasites resistant to these drugs from Southeast Asia to Africa, the Pacific, and South America. Only a few mutations in the parasite genome lead to resistance to chloroquine and sulfadoxine-pyrimethamine arising from indigenous parasites in Africa, Pacific, and South America.

Download or read book Characterization of Plasmodium Falciparum Resistance to Novel Drugs written by Sonia Edayé and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Plasmodium falciparum is the deadly protozoan parasite responsible for malaria. Malaria is one of the most important infectious diseases that has been raging for millennia and affecting almost half of the world's population. The treatment regimen that was based on quinoline drugs such as chloroquine (CQ), was efficient for decades. Nowadays, the use of this class of drugs is doomed to failure due to the emergence of quinoline-resistant parasites. Today, artemisinin-based combination therapies (ACTs) are the first-line drugs for uncomplicated falciparum malaria treatment. ACTs improve the cure rate of malaria and thus are seen as efficient treatment against uncomplicated forms of the disease. Despite their efficiency, these drugs are currently facing the development of resistance. PfCRT and PfMDR1, which are membrane transporters, have been shown to be involved in malaria parasites drug resistance. To tackle the inefficiency of existing drugs in regard to the development of resistance, alternative therapies must be discovered. In this thesis, antimalarial activity of novel potential drugs against P. falciparum is assessed and the interaction of these drugs with PfCRT and PfMDR1 is determined. Furthermore, because many ABC transporter genes play a key role in drug resistance, the characterization of an ABC transporter member of the ABCG family in Plasmodium is addressed and its role in drug resistance investigated.In the first part of this thesis, MK571 (a quinoline analogue) activity against P. falciparum parasites is investigated. MK571 is found to be more toxic to most of the CQ-resistant strains than to the CQ-sensitive strains. In addition, we determine that MK571 is not a substrate of PfCRT as are other quinoline drugs, but is instead a substrate of PfMDR1. Therefore, it can be a good complement to existing quinoline drugs in the treatment of uncomplicated malaria. In the second part, novel compound analogues of chloroquine are tested for their antimalarial activity against CQ-sensitive and -resistant parasites. Although chloroquine analogues tested possess the quinoline ring structure of chloroquine, they are less efficient than chloroquine and are not substrates of PfCRT. One of the analogues (3-ICQ) reverses the resistance of CQ-resistant strains to chloroquine and therefore, could be used in combination with chloroquine in cases of CQ-resistant malaria. In the third part of the thesis we conduct the characterization of PfABCG, the sole member of the P. falciparum ABCG family. The characterization study demonstrates that PfABCG is localized on the parasite plasma membrane and is expressed throughout the asexual life cycle of the parasite. In addition, PfABCG is differentially expressed in various Plasmodium strains. This expression does not correlate with the resistance to chloroquine but to the sensitivity of the parasite to an antihistaminic drug named ketotifen. Overall, this thesis sheds light on challenges and understanding of the complex resistance machinery deployed by the P. falciparum parasite from novel drug discovery to characterization of proteins. " --

Download or read book Vesicle Targeting in Plasmodium Falciparum written by Lawrence Sumanjah Ayong and published by . This book was released on 2009 with total page 174 pages. Available in PDF, EPUB and Kindle. Book excerpt: Proteins of the SNARE (Soluble N-ethylmaleimide sensitive factor attachment protein receptor) super-family have been characterized as playing an essential role in vesicle targeting and fusion in all eukaryotes. The intracellular malaria parasite Plasmodium falciparum exhibits an unusual endomembrane system that is characterized by an unstacked Golgi apparatus, a developmentally induced apical complex, and various organellar structures of parasite origin in the infected host cells. How malaria parasites target nuclear-encoded proteins to these novel compartments is a central question in Plasmodium cell biology. Ultrastructural studies elsewhere have implicated the participation of specialized vesicular elements in transport of virulence proteins, including various cytoadherance and host cell remodeling factors, into the infected erythrocyte cytoplasm. However, little is known about the machineries that define the directionality of vesicle trafficking in malaria parasites. We hypothesized that the P. falciparum SNARE proteins would exhibit novel features required for vesicle targeting to the parasite-specific compartments. We then identified for the first time and confirmed the expression of eighteen SNARE genes in P. falciparum. Members of the PfSNAREs exhibit atypical structural features (Ayong et al., 2007, Molecular & Biochemical Parasitology, 152(2), 113-122). Among the atypical PfSNAREs, PfSec22 contains an unusual insertion of the Plasmodium export element (PEXEL) within its profilin-like longin domain, preceded by an N-terminal hydrophobic segment.

Download or read book Molecular Characterization of a Rhoptry Antigen of Plasmodium Falciparum written by Heidi Juliette Brown and published by . This book was released on 1991 with total page 314 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Studies on the Molecular Basis of Chloroquine Resistance in Plasmodium Falciparum written by David James Johnson and published by . This book was released on 2003 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Molecular Characterization of the Ornithine Decarboxylase Gene of the Human Malaria Parasite Plasmodium Falciparum written by Lyn-Marié Birkholtz and published by . This book was released on 1998 with total page 129 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Biochemical Characterisation of the Plasmodium Falciparum Chloroquine Resistance Transporter written by Fadi Baakdah and published by . This book was released on 2020 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "The emergence of resistance to commonly used antimalarials significantly hindered global efforts in eliminating malaria and cost the human race losses of lives in millions. Plasmodium falciparum parasites are the most accountable for morbidity and mortality compared to the other species that infect humans. At the present time, artemisinin combination therapies is the approach used in the field to treat malaria infected people and has shown tremendous success. However, resistance to these combinations recently emerged and the pattern of progression and spreading is alarming. Chloroquine once was the first-line drug for treatment of malaria infected people, however, it became in-effective due to the spread of chloroquine resistant strains. Many attributes of chloroquine, at the time when it was effective, were desired and as such the field took on different approaches to revive it. Some people took an approach to withdraw the use of chloroquine for a significant period of time resulting in the emergence of chloroquine sensitive strains. Others looked into modifying the structure of chloroquine in order to make derivatives that would be an improvement on the original. Additionally, others went on to investigate the molecular mechanism by which the parasite confers resistance to chloroquine. Presently, it is well known that mutations in the chloroquine resistance transporter (PfCRT), expressed on the membrane of a lysosome-like organelle in the parasite, the digestive vacuole (DV), are the primary determinants of chloroquine resistance. The physiological role and normal substrates are still matters of speculation but the protein seems to be important for the parasite survival because knockout-PfCRT clones could not be established. The crystal structure was resolved showing the spatial arrangement of the polypeptide chain relative to the juxtaposition of the transmembrane domains forming the central cavity where drugs would interact with PfCRT. Given PfCRT’s role in chloroquine resistance, we thought if chloroquine was slightly modified it would bypass PfCRT resistance mechanism. The first experimental manuscript thesis, we examined the antimalarial activity of 16 novel chloroquine derivatives against chloroquine-sensitive and -resistant Plasmodium falciparum strains. Only two compounds (e.g., AQ-13 and AQ-129) showed effects that surpassed chloroquine’s effect on chloroquine resistant strains that were examined previously but not to the extent of their relationship with PfCRT. Our results demonstrate that AQ-13 and AQ-129 are poor substrates of PfCRT and thus more effective against chloroquine resistant parasites. In the 2nd manuscript, we describe the high resolution characterisation of an antiserum raised against the full-length C-terminal domain of PfCRT. An IgG pool that recognises a de-phosphorylated Ser411 epitope was extracted and used as a tool to monitor the phosphorylation status of residue Ser411. This pool of IgG`s identified the presence of an Ser411 de-phosphorylated homodimer form of PfCRT that does not localise to the DV membrane as does the monomer PfCRT. We also show that PfCRT monomer in chloroquine-sensitive strain (3D7) is significantly more phosphorylated than in chloroquine-resistant strain (Dd2-H) at Ser411, suggesting a possible functional role for this residue in drug resistance. In the last manuscript, we describe the adoption of mammalian HEK-293F cells as a heterologous system to study PfCRT function. Using HEK-293F cells stably expressing PfCRT wild-type and mutants, we show mutant-PfCRT to cause a significant acidification of the lysosomes, relative to wild-type PfCRT. We also provide direct evidence that acidification was mediated through mutant-PfCRT, since using a proline-165-modified mutant-PfCRT clone restored the acidification of lysosomes to wild-type PfCRT levels. Thus, results of this study show for the first time the role of Pro165 in mutant-PfCRT function"--

Download or read book Identification of Putative Plasmodium Falciparum Mefloquine Resistance Genes written by Mara L. Jeffress and published by . This book was released on 2004 with total page 344 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book In search of markers and mediators of chloroquine resistant plasmodium falciparum malaria written by Keir Robert Gregor McCutcheon and published by . This book was released on 2000 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: