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1
Modrzynska, Katarzyna Kinga. "Genetics of drug resistance in malaria : identification of genes conferring chloroquine and artemisinin resistance in rodent malaria parasite Plasmodium chabaudi." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/4888.
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Resistance to antimalarial drugs continues to be a major obstacle in controlling and eradicating malaria. The identification of genetic markers of resistance is vital for disease management but they can be difficult to predict before resistance arises in the field. This thesis describes an alternative approach to gene identification, combining an in vivo experimental evolution model, Linkage Group Selection (LGS) and Solexa genome re-sequencing. Here this model was used to resolve the genetic basis of chloroquine and artemisinin resistance in the rodent malaria parasite Plasmodium chabaudi. AS-30CQ is a parasite with high resistance to chloroquine and resistance to artemisinin. It was crossed with the genetically different drug-sensitive strain AJ. The resulting progeny were selected with drugs and backcrossed to the sensitive parent. Both crosses were treated with increasing concentrations of chloroquine and artemisinin. The frequency of markers from the sensitive parasite were analysed in order to characterize the signatures of drug selection. Three loci involved progressively in chloroquine resistance were identified on chromosomes 11, 3 and 2. One main locus on chromosome 2 was identified with artemisinin selection. The Solexa platform was used to re-sequence the genomes of both AS-30CQ and its sensitive progenitor, AS-sens. The differences between the two genomes were integrated with the LGS data to identify: 1) a strong candidate for the main CQresistance determinant - a putative amino acid transporter on chromosome 11 (aat1) 2) two candidates for high level chloroquine resistance on chromosome 3. and 3) a mutation in ubp1 gene on chromosome 2 that is likely to contribute to the highest level of chloroquine resistance and be main determinant of the artemisinin resistance phenotype. In addition the last section of this thesis describes two otherwise isogenic clones showing low- and high levels of chloroquine resistance were grown competitively to evaluate the effect of these mutations on parasite fitness. The highly resistant strain demonstrated a loss of fitness in relation to its more sensitive progenitor and was outcompeted in untreated and low-treated infections.
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Pokomi, Rostand Fankam. "Selection, synthesis and evaluation of novel drug-like compounds from a library of virtual compounds designed from natural products with antiplasmodial activities." University of the Western Cape, 2020. http://hdl.handle.net/11394/7950.
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Magister Pharmaceuticae - MPharm<br>Malaria is an infectious disease which continues to kill more than one million people every year and the African continent accounts for most of the malaria death worldwide. New classes of medicine to combat malaria are urgently needed due to the surge in resistance of the Plasmodium falciparum (the parasite that causes malaria in humans) to existing antimalarial drugs. One approach to circumvent the problem of P. falciparum resistance to antimalarial drugs could be the discovery of novel compounds with unique scaffolds and possibly new mechanisms of action. Natural products (NP) provide a wide diversity of compounds with unique scaffolds, as such, a library of virtual compounds (VC) designed from natural products with antiplasmodial activities (NAA) can be a worthy starting point.
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Gunsaru, Bornface. "Simplified Reversed Chloroquines to Overcome Malaria Resistance to Quinoline-based Drugs." PDXScholar, 2010. https://pdxscholar.library.pdx.edu/open_access_etds/400.
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Malaria is a major health problem, mainly in developing countries, and causes an estimated 1 million deaths per year. Plasmodium falciparum is the major type of human malaria parasite, and causes the most infections and deaths. Malaria drugs, like any other drugs, suffer from possible side effects and the potential for emergence of resistance. Chloroquine, which was a very effective drug, has been used since about 1945, but its use is severely limited by resistance, even though it has mild side effects, and is otherwise very efficacious. Research has shown that there are chloroquine reversal agents, molecules that can reinstate antimalarial activity of chloroquine and chloroquine-like drugs; many such reversal agents are composed of two aromatic groups linked to a hydrogen bond acceptor several bonds away. By linking a chloroquine-like molecule to a reversal agent-like molecule, it was hoped that a hybrid molecule could be made with both antimalarial and reversal agent properties. In the Peyton Lab, such hybrid "Reversed Chloroquine" molecules have been synthesized and shown to have better antimalarial activity than chloroquine against the P. falciparum chloroquine-sensitive strain D6, as well as the P. falciparum chloroquine-resistant strains Dd2 and 7G8. The work reported in this manuscript involves simplifying the reversal agent head group of the Reversed Chloroquine molecules, to a single aromatic ring instead of the two rings groups described by others; this modification retained, or even enhanced, the antimalarial activity of the parent Reversed Chloroquine molecules. Of note was compound PL154, which had IC50 values of 0.3 nM and 0.5 nM against chloroquine-sensitive D6 and chloroquine-resistant Dd2. Compound PL106 was made to increase water solubility (a requirement for bioavailability) of the simplified Reversed Chloroquine molecules. Molecular modifications inherent to PL106 were not very detrimental to the antimalarial activity, and PL106 was found to be orally available in mice infected with P. yoelli, with an ED50 value of about 5.5 mg/kg/d. Varying the linker length between the quinoline ring and the protonatable nitrogen, or between the head group and the protonatable nitrogen, did not have adverse effects on the antimalarial activities of the simplified Reversed Chloroquine molecules, in accord with the trends observed for the original design of Reversed Chloroquine molecules as found from previous studies in the Peyton Lab. The simplified Reversed Chloroquine molecules even tolerated aliphatic head groups (rather than the original design which specified aromatic rings), showing that major modifications could be made on the Reversed Chloroquine molecules without major loss in activity. A bisquinoline compound, PL192, was made that contained secondary nitrogens at position 4 of the quinoline ring (PL192 is a modification of piperaquine, a known antimalarial drug that contains tertiary nitrogens at position 4 of the quinoline ring); this compound was more potent than piperaquine which had an IC50 value of 0.7 nM against CQS D6 and an IC50 of 1.5 nM against CQR Dd2, PL192 had IC50 values of 0.63 nM against chloroquine sensitive D6 and 0.02 nM against chloroquine resistant Dd2. Finally, the mechanism of action of these simplified "Reversed Chloroquines" was evaluated; it was found that the simplified "Reversed Chloroquines" behaved like chloroquine in inhibiting β-hematin formation and in heme binding. However, the simplified "Reversed Chloroquines" were found to inhibit chloroquine transport for chloroquine resistant P. falciparum chloroquine resistance transporter expressed in Xenopus oocytes to a lesser extant than the classical reversal agent verapamil. From these studies it was noted that the simplified "Reversed Chloroquines" may not behave as well as classical reversal agents would in restoring chloroquine efficacy, but they are very potent, and so could be a major step in developing drug candidates against malaria.
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Bray, Patrick Gerrard. "Plasmodium falciparum : studies on the mechanism of chloroquine resistance and its reversal." Thesis, University of Liverpool, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.316597.
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Ursing, Johan. "Plasmodium Falciparum response to chloroquine and artemisinin based combination therapy (Act) in Guinea Bissau." Stockholm : Karolinska institutet, 2009. http://diss.kib.ki.se/2009/978-91-7409-695-8/.
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Liebman, Katherine May. "New 4-Aminoquinoline Compounds to Reverse Drug Resistance in P. falciparum Malaria, and a Survey of Early European Antimalarial Treatments." PDXScholar, 2014. http://pdxscholar.library.pdx.edu/open_access_etds/2114.
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Intermittent fevers caused by Plasmodium parasites have been known for millennia, and have caused untold human suffering. Today, millions of people are afflicted by malaria each year, and hundreds of thousands die. Historically, the most successful synthetic antimalarial drug was chloroquine, as it was safe, inexpensive, and highly efficacious. However, plasmodial resistance to chloroquine now greatly limits its utility. Previously in our laboratories it has been shown that attachment of a "reversal agent moiety" to the side chain of chloroquine can result in the restoration of activity against chloroquine-resistant strains of P. falciparum malaria. In the first part of the work presented here, a study has been made of the importance of the quinoline ring substitution pattern to the activity of such reversed chloroquines. The compounds presented here include those bearing a substituent in the 2-, 5, 6-, 7-, and/or 8- position, and include those with chloro, bromo, iodo, fluoro, nitro, trifluoromethyl, methyl, and methoxy substituents. For reversed chloroquines, 2-, 5-, and 8- substituents have been found to decrease in vitro antiplasmodial activity against P. falciparum relative to 7-chloro substitution, whereas 6- and 7- substituted compounds with various substituents have in many cases similar activity to that of 7-chloro substituted compounds. Little difference has been observed between 6- and 7- substitution, or between chlorine and a methyl group in position 6. In most cases these effects on activity are directionally similar to those observed for chloroquine analogs without an attached reversal agent, but the magnitude of the effect is generally smaller, suggesting that the activities of reversed chloroquines are less affected by modifications to the quinoline ring system than is true for chloroquine analogs without an attached reversal agent.
The second portion of this work presents an asymmetrical bis-quinoline (PL241) that is highly active against P. falciparum malaria, with an IC50 of less than 0.1 nM for all strains tested. Mechanistic studies have been performed in which the substitution patterns of the two quinoline rings of PL241 are modified in ways that indicate that either ring system is equally capable of participating in the antimalarial activity of these compounds. The excellent in vitro antiplasmodial activity of PL241 makes this a compound of great interest for further development as a potential antimalarial drug.
In the third part of this work, a survey has been made of antimalarial treatments recommended in the European medical literature from the time of Pliny the Elder (active in the first century A.D.) through the advent of modern malaria chemotherapy in the early twentieth century. In the fifteen primary sources utilized in this study, 251 distinct substances - primarily plants - were identified as having likely been used in the treatment of malaria. Of the 38 substances that were described in three or more sources, at least fifteen have been examined by other workers for antiplasmodial activity; in many cases, they were found to have antiplasmodial activity in vitro or in vivo. However, the majority of the phytotherapies for malaria identified in this project have not yet been tested against Plasmodium species, and may provide valuable leads in the search for new compounds active against drug-resistant malaria.
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Marijani, Theresia. "Modelling drug resistance in malaria." Thesis, Stellenbosch : University of Stellenbosch, 2009. http://hdl.handle.net/10019.1/4063.
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Ng, Anna. "Taste-masked and controlled-release formulations of chloroquine." Thesis, University College London (University of London), 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267929.
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Tesfaselassie, Elias Sibhatu. "Antimalarial Drug Discovery using Triazoles to Overcome Chloroquine Resistance." PDXScholar, 2015. https://pdxscholar.library.pdx.edu/open_access_etds/2506.
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Malaria is considered as one of the most prevalent and debilitating diseases affecting humans. Plasmodium falciparum is the most virulent form of the parasite which developed resistance to several antimalarial drugs. Chloroquine is one of the most successful antimalarials developed that is safe, effective, and cheap. However, its use has been limited due to the emergence of drug resistance. Click chemistry, particularly, the copper(I)-catalyzed reaction between azides and alkynes has shown to have a cutting-edge advantage in medicinal chemistry by its reliability, selectivity and biocompatibility.
Triazole-based antimalarials were synthesized via copper(I)-catalyzed alkyne-azide cycloaddition reaction by modifying the aliphatic chains terminal of chloroquine. The compounds synthesized contain triazole ring directly connected to an aromatic ring or via a piperazine linker. When tested for their in vitro antimalarial activity against D6, Dd2 and 7G8 strains of P. falciparum, 12 out of 28 compounds showed better activity against chloroquine resistant strains. Particularly, PL403 and PL448 exhibited potent activity than chloroquine against CQ-resistant strains Dd2 and 7G8, with IC50 values of 12.8 & 14.5 nM, and 15.2 & 11 nM respectively.
The efficiency of synthesizing several triazole-based antimalarials have proven click chemistry to be fast and efficient reaction. Generally, para-substitutions and di-substitutions with electron-withdrawing groups were found to be beneficial for having better antimalarial activity for these group of click compounds. Moreover, the incorporation of piperazine linker has brought an enhanced antimalarial activity.
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Abrahem, Abrahem F. "Mechanisms of drug resistance in malaria." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0033/MQ50704.pdf.
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Carlton, Jane M. R. "The genetics of chloroquine resistance in the rodent malaria parasite Plasmodium chabaudi." Thesis, University of Edinburgh, 1995. http://hdl.handle.net/1842/13312.
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The aim of this work has been to use linkage analysis to determine the chromosomal location of genes involved in chloroquine resistance in the rodent malaria parasite <I>Plasmodium chabaudi</I>. The <I>P. chabaudi</I> genome was found to contain 14 chromosomes. A genetic map of each chromosome was made using DNA markers. Most of the markers were known genes from other species of <I>Plasmodium</I>. Other markers were developed by the RAPD-PCR (random amplified polymorphic DNA-polymerase chain reaction) technique, the first time this method has been developed for use with <I>Plasmodium</I> parasites. In total, more than 100 markers were mapped to individual <I>P. chabaudi</I> chromosomes. Two important markers were cloned from <I>P. chabaudi</I> DNA using PCR. (i) the <I>P. chabaudi</I> homologue (<I>pcmdr1</I>) of the multiple drug resistance gene of <I>P.falciparum (pfmdr 1</I>); this has been implicated in the mechanism of chloroquine-resistance in <I>P. falciparum</I>. (ii) a possible homologue of the <I>P. falciparum</I> marker pS590.7, which has been claimed to be linked to a chloroquine-resistance locus in <I>P. falciparum</I>. 13 genetically distinct clones from the cross were phenotyped for their susceptibility to chloroquine. 8 were found to be resistant and 5 sensitive. These clones were analysed for their inheritance of 46 polymorphic markers. This revealed that neither <I>pcmdr 1</I> nor the putative ps590.7 homologue were linked to chloroquine resistance in this cross. 12 of the 13 progeny showed linkage disequilibrium with a locus on chromosome 11. Statistical analysis showed the linkage to be significant, with a probability of 0.05>P>0.03. The work submitted here represents the first in-depth genetic analysis of a <I>P. chabaudi</I> cross and identifies a locus which may be involved in the genetic mechanism of chloroquine resistance.
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Obua, Celestino. "Fixed-dose chloroquine and sulfadoxine/pyrimethamine treatment of malaria : outcome and pharmacokinetic aspects /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-144-9/.
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Hafiz, Rehan A. "The role of cytochrome P450 and P-glycoprotein in the development of resistance by Plasmodium falciparum to chloroquine." Thesis, University of Aberdeen, 1994. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU068608.
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1. Drug resistant strains of <I>P. falciparum</I> are becoming increasingly prevalent in most malaria endemic areas of the world, complicating treatment and prophylaxis. The prevalence of <I>P. falciparum</I> was assessed in six villages in the Punjab, Pakistan. The study was carried out during the months of August-October, 1992. A total of 566 people was surveyed. Fifty blood samples from positive plasmodial cases were analysed. Overall <I>P. falciparum</I> comprised the highest proportion of cases (62.39%) followed by <I>P. vivax</I> (36.7%) and mixed infection (0.85%) and mixed infection (0.85%). The slide positivity rate was 20.6%. The prevalence rate of plasmodial infection in the combined population was 3.8/1000. This is higher than the reported national prevalence rate of 0.7/1000 (WHO, 1992). 2. Sensitivity to chloroquine of the cultured isolates was carried out by [<sup>3</sup>H]hypoxanthine incorporation and by microscopical assessment. 3. In mammalian cells mixed function oxidase systems of which cytochrome P450 is the terminal oxidase are responsible for the metabolism of a whole variety of structurally unrelated xenobiotics, which include antimalarial drugs. 4. An alternative method of resistance was investigated by examining the relationship between resistance and chloroquine accumulation and efflux in <I>P. falciparum</I> using [<sup>3</sup>H]chloroquine. 5. Verapamil, a calcium channel blocker has been shown to reverse completely chloroquine-resistance in chloroquine-resistant <I>P. falciparum</I> isolates. 6. The digestive vacuole is thought to be the site of action of chloroquine on the malarial parasite. 7. The ultimate target of chloroquine and related drugs remains unclear. Drug resistance may be a result of decreased vacuolar accumulation in chloroquine-resistant parasites.
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Taylor, Dale. "The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria." Doctoral thesis, University of Cape Town, 2012. http://hdl.handle.net/11427/14394.
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Although several dozen different compounds are able to transiently alter chloroquine resistance via chemosensitisation, the phenomenon has never evolved beyond laboratory practice as a result of in vivo difficulties. Chemosensitising compounds either need to be administered at doses which are toxic to the host in order to reverse resistance, or the drug is so highly bound to serum proteins that there is an insufficient circulating quantity available to restore sensitivity. Nine chemosensitisers were evaluated in vitro against several resistant isolates of the malaria parasite in order to develop a cocktail treatment of three compounds which could reverse resistance additively or synergistically when used at low doses with chloroquine. This would bypass any toxicity issues which might arise from the use of a high dose of a single agent. Six of the chemosensitisers were selected for combination into six different cocktails which were tested in vitro. Each cocktail contained one antidepressant, one antihistamine and one antipsychotic. Low doses of each drug were able to alter resistance to a small extent singly and in combination; this was shown by determining the effect of drugs and cocktails on both chloroquine transport using radiolabelled chloroquine, and chloroquine efficacy using the lactate dehydrogenase assay for parasite viability. The reversal activity was shown to be additive in the cocktail treatments and not synergistic, and was highly dose-dependent. There was no direct correlation between the change in chloroquine transport and the extent of resistance reversal. The chemosensitisers' effect on chloroquine transport was evaluated in a mouse model of malaria and shown to be similar to that seen against cultured human parasites; following this, the cocktails were tested for efficacy in mice infected with chloroquine-resistant malaria. Five of the six cocktails were able to significantly alter parasite survival in the mice in conjunction with a low dose of chloroquine. Drug levels in the mice were quantified via mass spectrometry and liquid chromatography in order to correlate the efficacy data. One of the compounds in the failed treatment was shown to circulate at low levels in the animals and this is possibly why that treatment, although effective in vitro, did not yield a result in vivo.
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Ndifor, Anthony Mbisah. "Drug metabolism in malaria parasites and its possible role in drug resistance." Thesis, University of Liverpool, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317180.
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Fortuin, Elton E. "Novel aminoquinoline-polycyclic hybrid molecules as potential antimalarial agents." University of the Western Cape, 2014. http://hdl.handle.net/11394/4463.
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Magister Pharmaceuticae - MPharm<br>Plasmodium falciparum malaria continues to be a worldwide health problem, especially in developing countries in Africa and is responsible for over a million fatalities per annum. Chloroquine (CQ) is low-cost, safe and was the mainstay aminoquinoline derived chemotherapeutic agent that has been used for many years against blood-stage malaria. However, today the control of malaria has been complicated by increased resistance of the malaria parasite to existing antimalarial agents such as CQ. The primary cause of resistance is mutation in a putative ATP-powered multidrug efflux pump known as the p-glycoprotein (pGP) pump, and point mutation in P. falciparum CQ resistance transporter (PfCRT) protein. These mutations are responsible for the reduced accumulation of CQ at its primary site of action, the acidic digestive food vacuole of the parasite.To overcome the challenges of CQ resistance in P. falciparum, chemosensitiser offer an attractive approach. Chemosensitisers or reversal agents are structurally diverse molecules that are known to reverse CQ resistance by inhibiting the pGP efflux pump and/or the PfCRT protein associated with CQ export from the digestive vacuole in CQ resistant parasites. Chemosensitisers include the well-studied calcium channel blocker verapamil and antihistaminic agent chlorpheniramine. These drugs have little or no inherent antimalarial activity but have shown to reverse CQ resistance in P. falciparum when co-administered with CQ. Because of the channel blocking abilities of pentacycloundecylamines (PCUs) such as NGP1-01, it is postulated that these agents may act as chemosensitisers and circumvent the resistance of the Plasmodium parasite against CQ. Therefore as a proof of concept we conducted an experiment using CQ co- administered with different concentrations of NGP1-01 to evaluate the ability of NGP1-01 to act as a chemosensitiser.Herein, we report the ability of NGP1-01, the prototype pentacycloundecylamine (PCU), to reverse CQ resistance (> 50 %) and act as a chemosensitiser. NGP1-01 alone exhibited very low intrinsic antimalarial activity against both the resistant and sensitive strain (> 2000 nM), with no toxicity to the parasite detected at 10 µM. A statistically significant (p < 0.05) dose dependent shift was seen in the CQ IC50 values at both 1 µM and 10 µM concentration of co-administeredNGP1-01 against the resistant strain. Based on this finding we set out to synthesise a series of novel agents comprising of a PCU moiety as the reversal agent (RA) conjugated to a CQ-like aminoquinoline (AM) molecule and evaluate the potential of these PCU-AM derivatives as antimalarial- and/or reversed CQ agents. As recently shown by Peyton et al., (2012), the conjugation of a CQ-like molecule with a RA such as the chemosensitiser imipramine and derivatives thereof is a viable strategy to reverse CQ resistance in multidrug-resistant P. falciparum. The novel compounds were obtained by amination and reductive amination reactions. The synthetic procedures involved the conjugation of the Cookson’s diketone with different tethered 4-aminoquinoline moieties to yield the respective carbinolamines and the subsequent imines. This was followed by a transannular cyclisation using sodium cyanoborohydride as reducing agent to yield the desired PCU-AM derivatives. The CQ-like AMderivatives were obtained using a novel microwave (MW) irradiation method. Structure elucidation was done by utilising 1H- and 13C NMR spectroscopy as well as IR absorption spectrophotometry and mass spectrometry. Five PCU-AM reversed CQ derivatives were successfully synthesised and showed significant in vitro antimalarial activity against the CQ sensitive strain (NF54). PCU-AM derivatives 1.1 – 1.4 showed antimalarial IC50 values in the ranges of 3.74 – 17.6 ng/mL and 27.6 – 253.5 ng/mL against the CQ-sensitive (NF54) and CQ-resistant strains (Dd2) of Plasmodium falciparum, respectively. Compound 1.1 presented with the highest antimalarial activity against both strains and was found to be 5 fold more active against the resistant strain than CQ. The reversed CQ approach resulted in improved resistance reversal and a significantly lower concentration PCU was required compared to NGP1-01 and CQ in combination. This may be attributed to the improved ability of compound 1.1 to actively block the pGP pump and/or the increased permeability thereof because of the lipophilic aza-PCU moiety. Compound 1.1 also showed the lowest RMI value confirming that this compound has the best potential to act as a reversed CQ agent in the series. Cytotoxicity IC50 values observed for compounds 1.1 – 1.4 were in the low micromolar concentrations (2.39 – 9.54 µM) indicating selectivity towards P. falciparum (SI = 149 – 2549) and low toxicity compared to the cytotoxic agent emetine (IC50 = 0.061 µM).These results indicate that PCU channel blockers and PCU-AM derived conjugates can be utilised as lead molecules for further optimisation and development to enhance their therapeuticpotential as reversal agents and reversed CQ compounds.
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Maude, Richard James. "Malaria elimination modelling in the context of antimalarial drug resistance." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:3a5321ca-f8fc-45b2-a002-363d982d3cc5.
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Introduction: Antimalarial resistance, particularly artemisinin resistance, is a major threat to P. falciparum malaria elimination efforts worldwide. Urgent intervention is required to tackle artemisinin resistance but field data on which to base planning of strategies are limited. The aims were to collect available field data and develop population level mathematical models of P. falciparum malaria treatment and artemisinin resistance in order to determine the optimal strategies for elimination of artemisinin resistant malaria in Cambodia and treatment of pre-hospital and severe malaria in Cambodia and Bangladesh. Methods: Malaria incidence and parasite clearance data from Cambodia and Bangladesh were collected and analysed and modelling parameters derived. Population dynamic mathematical models of P. falciparum malaria were produced. Results: The modelling demonstrated that elimination of artemisinin resistant P. falciparum malaria would be achievable in Cambodia in the context of artemisinin resistance using high coverages with ACT treatment, ideally combined with LLITNs and adjunctive single dose primaquine. Sustained efforts would be necessary to achieve elimination and effective surveillance is essential, both to identify the baseline malaria burden and to monitor parasite prevalence as interventions are implemented. A modelled policy change to rectal and intravenous artesunate in the context of pre-existing artemisinin resistance would not compromise the efficacy of ACT for malaria elimination. Conclusions: By being developed rapidly in response to specific questions the models presented here are helping to inform planning efforts to combat artemisinin resistance. As further field data become available, their planned on-going development will produce increasingly realistic and informative models which can be expected to play a central role in planning efforts for years to come.
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Certain, Laura K. "Genetic profiling of drug resistance in Plasmodium falciparum /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/10252.
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Matthews, Amanda. "A Mathematical Model for Anti-Malarial Drug Resistance." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1721.
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Despite the array of medical advances of our modern day society, infectious diseases still plague millions of people worldwide. Malaria, in particular, causes substantial suffering and death throughout both developed and developing countries. Aside from the socioeconomic challenges presented by the disease's prevalence in impoverished nations, one of the major difficulties scientists have encountered while attempting to eradicate the disease is the parasite's ability to become resistant to new drugs and methods of treatment. In an effort to better understand the dynamics of malaria, we analyze a mathematical model that accounts for both the treatment aspect as well as the drug resistance that accompanies it. Simulations demonstrating the effects of treatment rates and the level of resistance are studied and discussed in hopes of shedding additional light on the characteristics of this devastating epidemic.
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Eriksen, Jaran. "Managing childhood malaria in rural Tanzania : focusing on drug use and resistance /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-678-6/.
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Huijben, Silvie. "Experimental studies on the ecology and evolution of drug-resistant malaria parasites." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/3945.
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Drug resistance is a serious problem in health care in general, and in malaria treatment in particular, rendering many of our previously considered ‘wonder drugs’ useless. Recently, large sums of money have been allocated for the continuous development of new drugs to replace the failing ones. We seem to be one step behind the evolution of antimalarial resistance; is it possible to get one step ahead? Are interventions which slow down the evolution and spread of drug-resistant malaria parasites achievable? In this thesis, I address these issues with experimental data, using the well-established rodent malaria model Plasmodium chabaudi to understand the selective advantages and disadvantages drug-resistant parasites endure within a vertebrate host and the selective pressures various drug treatment regimes exert on these parasites. Competitive interactions between drug-resistant and drug-sensitive parasites were observed within the host, with resistant parasites having a competitive disadvantage in the absence of drug treatment. The frequency of resistant parasites at the start of the infection was an important determinant of the strength of selection: the lower their frequency, the stronger the competitive suppression in non-treated hosts and the greater their competitive release following drug treatment. Genetically similar genotypes, one resistant and one sensitive, showed similar dynamics following drug treatment. Multiplicity of infection did not have an effect on the within-host dynamics: a larger number of co-infecting susceptible genotypes did not lead to greater competitive suppression or release of resistant parasites. Lastly, various drug treatment regimes were compared. Conventional drug treatment resulted in the greatest selective advantage for drug-resistant parasites, while less aggressive treatments were equally as effective, or even better, at improving host health and reducing overall infectiousness. These studies demonstrate that altering the within-host ecology of drug-resistant parasites by administering drugs and hence removing the drug-sensitive competitors has a large influence on the transmission potential of drug-resistant parasites. Furthermore, this thesis provides proof of principle that other drug treatment regimes different from those currently in use could better control drug-resistant parasites, without compromising other treatment goals. In the case of malaria, less drugs may mean extending the useful lifespan of that drug.
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Makowa, Hazel Beverly. "The relationship between the insecticide dichloro-diphenyl-trichloroethane and chloroquine in Plasmodium falciparum resistance." Thesis, Stellenbosch : Stellenbosch University, 2012. http://hdl.handle.net/10019.1/20310.
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Thesis (MSc)--Stellenbosch University, 2012.<br>ENGLISH ABSTRACT: Dichloro-diphenyl-trichloroethane (DDT) was extensively used in agriculture pest control and
is still used for indoor residual spraying to control malaria. The lipophylicity of DDT and its
breakdown product dichloro-diphenyl-dichloroethylene (DDE) dictates that they associate
with membranes, lipids and hydrophobic proteins in the biological environment. Their poor
degradable nature causes DDT and DDE to persist for decades in the environment and in
individuals who are or were in contact with the pesticide. In many countries the synchronised
resistance of the mosquito vector to insecticides and the malaria parasite towards antimalarial
drugs led to a drastic rise in malaria cases and to malaria epidemics. This study assesses the
influence of low level exposure of DDT and DDE on chloroquine (CQ) resistance of the dire
human malaria parasite, Plasmodium falciparum.
The in vitro activity of p,p’-DDT and p,p’-DDE towards blood stages of chloroquine sensitive
(CQS) P. falciparum D10 and chloroquine resistant (CQR) P. falciparum Dd2 was
determined using two complementary in vitro assays (Malstat and SYBR Green 1). The 50%
inhibition concentrations (IC50s) of p,p’-DDT and p,p’-DDE were found to be ±14 to 38 μM
(5-12 μg/mL) and highly similar towards CQS and CQR P. falciparum strains. This result
indicated that the proteins involved in CQ resistance have no effect on the activity of the
insecticide DDT and it breakdown product DDE.
In order to assess the influence of DDT and DDE on CQ activity, in vitro fixed ratio drug
combination assays were performed, as well as isobologram analysis. We found that CQ
works in synergy with p,p’-DDT and p,p’-DDE against CQS P. falciparum D10. However,
both p,p’-DDT and p,p’-DDE were antagonistic toward CQ activity in CQR P. falciparum
Dd2. This indicated that p,p’-DDT and p,p’-DDE do have an effect on CQ resistance or on
the action of CQ via a target other than hemozoin polymerization. The observation of
reciprocal synergism of p,p’-DDT and p,p’-DDE with CQ against CQS D10 and antagonism
against CQR Dd2 strain is highly significant and strongly indicates selection of CQ resistant
strains in the presence of p,p’-DDT and p,p’-DDE. People who have low levels of circulating
DDE and/or DDT could be at a high risk of contracting CQR malaria. However, medium term
(nine days) DDE exposure of CQS P. falciparum D10 did not induce resistance, as no
significant change in activity of CQ, p,p’-DDT and p,p’-DDE towards blood stages the CQS
strain was observed. This exposure was, however, shorter than expected for a malaria
infection and would be addressed in future studies.
From our results on the interaction of CQ with p,p’-DDT and p,p’-DDE, it was important to
assess the residual DDT and DDE variable and how much of residual p,p’-DDT and/or p,p’-
DDE would enter into or remain in the different compartments (the RPMI media, erythrocytes
and infected erythrocytes) over time. In combination with liquid-liquid extraction, we
developed a sensitive GC-MS analyses method and a novel HPLC-UV analysis method for
measuring DDT and DDE levels in malaria culturing blood and media. Whilst the HPLC-UV
method was relatively cheaper, faster, and effective in determining high DDT and DDE
concentrations, the optimised GC-MS method proved to be effective in detecting levels as
low as 78 pg/mL (ppt) DDE and 7.8 ng/mL (ppb) DDT in biological media. Using both the
HPLC and GC-MS methods we observed that malaria parasites influence distribution of the
compounds between the erythrocytic and media fractions. P. falciparum D10 infection at
±10% parasitemia lead to must faster equilibration (less than 8 hours) between compartments.
Equimolar distribution of p,p’-DDE was observed, but the parasites lead to trapping of the
largest fraction of p,p’-DDT in the erythrocyte compartment. These results indicate that a
substantial amount would reach the intra-erythrocytic parasite and could influence the
parasite directly, possibly leading to either synergistic or antagonistic drug interactions.
This study is the first to illustrate the “good and bad” of the insecticide DDT in terms of CQ
resistance and sensitivity toward the human malaria parasite P. falciparum. These results will
hopefully have an important influence on how future policies on malaria control and
treatment particularly in endemic areas will be addressed and could also have an impact on
the anti-malarial drug discovery approach.<br>AFRIKAANSE OPSOMMING: Dichlorodifenieltrichloroetaan (DDT) is op groot skaal in landbouplaagbeheer gebruik en
word nog steeds gebruik vir binnenshuise oppervlakbespuiting om malaria te beheer. Die
lipofilisiteit van DDT en sy afbraakproduk dichlorodifenieldichloroetileen (DDE) dikteer dat
hulle met membrane, lipiede en hidrofobiese proteïene in die biologiese omgewing
assosieer. Stadige afbraak veroorsaak dat DDT en DDE vir dekades in die omgewing
agterbly, asook in individue wat in kontak is, of was met die insekdoder. In baie lande het
gesinkroniseerde weerstand van die muskietvektor teenoor insekdoders en die malariaparasiet
teenoor antimalariamiddels gelei tot 'n drastiese styging in malariagevalle en tot malariaepidemies.
In hierdie studie word die invloed van lae vlak blootstelling van DDT en DDE op
chlorokien (CQ) weerstand van die mens malariaparasiet, Plasmodium falciparum,
geëvalueer.
Die in vitro aktiwiteit van p,p'-DDT en p,p'-DDE teenoor die bloedstadia van chlorokiensensitiewe
(CQS) P. falciparum D10 en chlorokien-weerstandbiedende (CQW) P. falciparum
Dd2 is bepaal deur gebruik te maak van twee komplementêre in vitro toetse (Malstat en
SYBR Groen toetse). Die 50% inhibisie konsentrasies (IC50s) van p,p'-DDT en p,p'-DDE is
bepaal as ±14 to 38 μM (5-12 μg/mL) en was hoogs vergelykbaar tussen CQS en CQW P.
falciparum stamme. Hierdie resultaat het aangedui dat die proteïene betrokke by CQ
weerstand geen effek op die aktiwiteit van die insekdoder DDT en die afbraakproduk DDE
het nie.
Om die invloed van DDT en DDE op CQ aktiwiteit te evalueer, is die aktiwiteit van
kombinasies van die verbindings in vaste verhoudings getoets, tesame met isobologram
ontleding. Ons het gevind dat CQ sinergisties saam met p, p'-DDT en p, p'-DDE teen CQS P.
falciparum D10 werk. Daarteenoor het beide p, p'-DDT en p, p'-DDE antagonistiese werking
getoon teenoor CQ aktiwiteit met CQW P. falciparum Dd2 as teiken. Dit het aangedui dat
p,p'-DDT en p, p'-DDE wel 'n invloed op CQ weerstand het of ‘n aktiwiteit van CQ, anders as
hemozoin polimerisasie, beïnvloed. Die waarneming van resiproke sinergisme en
antagonisme van p, p'-DDT en p, p'-DDE in kombinasie met CQ teenoor die CQS D10 en
CQW DD2 stamme respektiewelik, is hoogs betekenisvol en dui op seleksie van CQweerstandige
stamme in die teenwoordigheid van p, p'- DDT en p, p'-DDE. Mense wat lae
vlakke van sirkulerende DDE/DDT het, het dus 'n hoër risiko om CQW malaria te kry.
Verder is gevind dat medium termyn (nege dae) DDE blootstelling van CQS P. falciparum
D10 nie weerstand nie veroorsaak nie, want geen beduidende verandering in die aktiwiteit
van CQ, p,p'-DDT en p,p'-DDE teenoor die bloed stadiums van die CQS stam is waargeneem
nie. Hierdie blootstelling is egter korter as in 'n malaria-infeksie en sal verder bestudeer word
in toekomstige studies.
Vanuit die interaksie resultate van CQ met p, p'-DDT en p, p'-DDE was dit belangrik om die
residuele DDT en DDE veranderlike te evalueer, asook die distribusie van p,p'-DDT en p,p'-
DDE tussen die verskillende kompartemente (die kultuurmedium, eritrosiete en geïnfekteerde
rooibloedselle) oor verloop van tyd. In kombinasie met vloeistof-vloeistof ekstraksie, het ons
'n sensitiewe GC-MS en nuwe HPLC-UV analisemetode ontwikkel vir die meet van DDT en
DDE-vlakke in bloed (normale en geïnfekteerde eritrosiete) en die kultuurmedium. Terwyl
die HPLC-UV metode relatief goedkoper, vinniger en effektief in die bepaling van hoë DDT
en DDE-konsentrasies is, was die geoptimaliseerde GC-MS metode doeltreffend in die
opsporing van vlakke so laag as 78 pg/mL (dpt) DDE en 7.8 ng/mL (dpb) DDT in biologiese
media. Met behulp van beide die HPLC-UV en GC-MS metodes is waargeneem dat die
malariaparasiet die ekwilibrasie van die verbindings tussen die eritrosiet- en media
kompartemente beïnvloed. P. falciparum D10 infeksie met ± 10% parasitemia lei tot vinniger
ekwilibrasie (minder as 8 uur) tussen die kompartemente. Ekwimolêre verspreiding van p,p'-
DDE is waargeneem, maar die parasiete het die grooste fraksie van p,p'-DDT in die eritrosiet
kompartement vasgevang. Hierdie resultate wys dat 'n aansienlike fraksie die intraeritrositiese
parasiet kan bereik en sodoende die parasiet direk kan beïnvloed en moontlik kan
lei tot sinergistiese of antagonistiese middel interaksies.
Hierdie studie is die eerste om die "goed en sleg" van die insekdoder DDT in terme van CQ
weerstand en sensitiwiteit teenoor die menslike malariaparasiet P. falciparum te
illustreer. Hierdie resultate sal hopelik 'n belangrike invloed hê op die toekomstige beleid oor
die beheer van malaria en behandeling, veral in endemiese gebiede, en mag ook 'n impak hê
op die antimalariamiddel navorsing.
23
Haupt, Hayley Claire. "Exploring the potential of chloroquine and quinacrine derivatives as new antiprotozoal and tumour drug resistance reversal agents." Master's thesis, University of Cape Town, 2002. http://hdl.handle.net/11427/6974.
Full textAbstract:
Bibliography: leaves 108-113.<br>Compounds containing the quinoline and acridine moieties have been utilized extensively in the search for new antiprotozoal and multidrug resistance reversal agents. Hence, these moieties formed the basis for the synthesis of new compounds. New sulfonamides, ureas and amine analogues were synthesized and evaluated for inhibitory activity against trypanothione reductase (TryR), in vitro activity against the causative agents of trypanosomiasis, leishmaniasis as well as chloroquine-sensitive and resistant malaria. Some were also evaluated as potential tumour multidrug resistance reversal agents.
24
Marfurt, Jutta. "Drug resistant malaria in Papua New Guinea and molecular monitoring of parasite resistance /." Basel : [s.n.], 2006. http://edoc.unibas.ch/diss/DissB_8080.
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Blake, Lynn Dong. "Antimalarial Exoerythrocytic Stage Drug Discovery and Resistance Studies." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6182.
Full textAbstract:
Malaria is a devastating global health issue that affects approximately 200 million people yearly and over half a million deaths are caused by this parasitic protozoan disease. Most commercially available drugs only target the blood stage form of the parasite, but the only way to ensure proper elimination is to treat the exoerythrocytic stages of the parasite development cycle. There is a demand for the discovery of new liver stage antimalarial compounds as there are only two current FDA approved drugs for the treatment of liver stage parasites, one of which fails to eliminate dormant forms and the other inducing hemolytic anemia in patients with G6PD deficiency. In efforts to address the dire need for liver stage drugs, we developed a high-throughput liver stage drug-screening assay to identify liver stage active compounds from a wide variety of chemical libraries with known blood stage activity. The liver stage screen led us to further investigate an old, abandoned compound known as menoctone. Menoctone was developed as a liver stage active antimalarial, however, the development of more potent compounds led to the abandonment of further menoctone research. Our research demonstrated that resistant parasites can transmit mutations through mosquitoes, which was previously believed to not be possible. Furthermore, we studied a novel genetic marker that may indicate potential resistance against malaria parasite infection and the cytotoxic effects associated with the disease. Future experiments aim to identify and advance our methods for the elimination of Plasmodium exoerythrocytic parasites.
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Certad, Gabriela. "Characterization of drug-resistant isolates of Plasmodium falciparum." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0017/MQ37102.pdf.
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Ochekpe, N. A. "Some applications of HPLC in the biguanide antimalarial drugs." Thesis, Open University, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383660.
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Brockman, Al. "In Vitro and genetic studies of Plasmodium Falciparum drug resistance in Northwestern Thailand /." [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18970.pdf.
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Beau, Jeremy. "Drug Discovery from Floridian Mangrove Endophytes." Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4287.
Full textAbstract:
A significant challenge of the 21st century is the growing health threat stemming from drug-resistant infectious diseases. There is an undeniable need to discover new, safe and effective drugs with novel mechanisms of action to combat this threat. A study of drugs currently on the market showed that natural products account for approximately 75% of new anti-infective drugs, either as new agents or analogs based upon their structure. Unfortunately, major pharmaceutical companies have cut back tremendously in natural products research in part due to the frustrating obstacle of frequent rediscovery of compounds. Fungi in particular are difficult to work with in that they do not always produce the same variety and quantities of secondary metabolites under laboratory conditions. One of the groundbreaking discoveries evolving from genomics research is the observation that many fungi possess more gene clusters encoding for the production of secondary metabolites than the reported number of natural products isolated from those organisms. Simple epigenetic modifications such as DNA methlytransferase or histone deacetylase inhibition can activate silenced genes leading to the genesis of novel chemistry from the fungus. The work presented herein is a study of the isolation and characterization of anti-infective compounds from Floridian mangrove endophytes. In addition, epigenetic modifications were explored in order to increase the production of secondary metabolites as well as for the purpose of generating new analogs not found in the controls. Finally, structure activity relationship studies were performed in order to maximize the anti-malarial and antibiotic activity of cytosporone E.
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Henriques, G. "Exploring the contribution of new genetic markers of drug resistance in human malaria parasites." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2015. http://researchonline.lshtm.ac.uk/2212899/.
Full textAbstract:
Antimalarial drugs remain as one of the most powerful tools in the fight against malaria with artemisinin derivatives now standing as the cornerstone of anti-malarial drug therapy. Unfortunately, evidence of delayed in vivo parasite clearance after artemisinin treatment is accumulating on the Thai-Cambodian border and in nearby countries. A better understanding of the mechanisms of artemisinin (ART) resistance may contribute to the development and validation of new tools for the surveillance of resistance. One promising approach to identifying candidate genetic markers of ART resistance is genetic analysis of drug-pressured mutants of the rodent malaria parasite Plasmodium chabaudi. This experimental system has identified a number of genetic mutations in parasites artificially selected for resistance to ART derivatives. These mutations encode alterations in a de-ubiquitinating enzyme (UBP-1) and in a 26S proteasome subunit (26SPS), both involved in the ubiquitin-proteasome pathway, responsible for protein turnover through selective degradation. An additional mutation was found to have occurred in a gene encoding the “mu” chain of the AP2 adaptor protein complex, a component of the endocytic machinery. The importance of the above mentioned markers in modulating susceptibility to different drugs in the human malaria parasite remains unclear. In that context, the hypothesis to be tested in this thesis is that the three loci implicated in ART resistance in experimentally selected in P. chabaudi will similarly modify ART response in natural parasite populations of P. falciparum. Increased artemisinin resistance in a P. chabaudi parasite derived from a chloroquine resistant parasite after prolonged and progressive artemisinin selection was phenotypic and genetically characterized. The whole genome sequencing identified a mutation in a gene encoding the mu chain of the AP2 adaptor protein complex. To explore the genetic variability of the ap2-mu gene in P. falciparum and its associations with artemisinin in vitro responses we sequenced field isolates from Brazil, São Tomé and Rwanda. Analysis of P. falciparum field isolates showed a weak association between a Ser160Asn mutation and in vitro dihydroartemisinin responses. To investigate the correlation between polymorphisms in pfubp-1 and pfap2-mu and in vivo parasite susceptibility to ART we genetically characterized samples from an ACT clinical trial carried out in Kenya. Previously work done on the same ACT clinical trial samples described sub-microscopic persistent parasites on day 3 post-treatment samples. These parasites were only detected by qPCR but the children carrying these parasites had a higher transmission potential and were far more likely to go on to classical treatment failure at day 28 or day 42 post-treatment. The molecular work carried out here demonstrates that a Ser160Asn/Thr mutation in the pfap2-mu gene and an E1528D mutation in the pfubp-1 gene might be associated with in vivo responses to artemisinin derivatives. Polymorphisms on the pfubp-1 gene and pfap2-mu genes were further studied using field isolates from an ACT clinical trial in Burkina-Faso which were also tested in vitro for their response to dihydroartemisinin and several other antimalarial drugs. Using these samples, we also investigate the genetic polymorphisms of the pf26S-protSU, another drug resistant candidate gene identified in the studies of P. chabaudi. Data revealed that polymorphisms in pfubp1 and pf26S-protSU, can modulate in vitro responses to lumefantrine. However, this work did not reveal any significant association between polymorphisms in pfubp-1 and pfap2-mu genes and in vitro artemisinin susceptibilities or treatment outcomes. In order to validate the pfap2-mu candidate marker as an important modulator of parasite sensitivity to artemisinins and to improve understanding of the biological mechanisms of resistance to this class of drugs we further performed gene functional characterization using transfection techniques. Transgenic parasites carrying the 160Asn allele of pfap2-mu were significantly less sensitive to dihydroartemisinin using a standard in vitro test. Sensitivity to chloroquine and quinine were also reduced. Localization studies of pfap2-mu were performed by transfection of fluorescent-tagged gene construct into P. falciparum and expression of fluorescent fusion protein in parasites was observed using a confocal microscope. The findings from this study provide the first in vivo evidence that polymorphisms in the pfap2-mu and pfubp-1 genes modulate P. falciparum responses to artemisinins. Additionally, transgenic laboratory lines of P. falciparum carrying the 160Asn mutation in pfap2-mu gene have altered in vitro responses to dihydroartemisinin, quinine and chloroquine. We therefore propose these genes should be evaluated further as potential molecular markers of artemisinin resistance.
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Dlamini, Sabelo Vusi. "Malaria in Swaziland : disease incidence and prevalence of molecular markers of antimalarial drug resistance." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.536875.
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Low, Chee Kin Andrew. "Characterisation and evaluation of novel potential target (tubulin) for antimalarial chemotherapy /." Access via Murdoch University Digital Theses Project, 2004. http://wwwlib.murdoch.edu.au/adt/browse/view/adt-MU20050930.125714.
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Ross, Leila Saxby. "Harnessing Evolutionary Fitness in Plasmodium falciparum for Drug Discovery and Suppressing Resistance." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11119.
Full textAbstract:
Malaria is a preventable and treatable disease caused by infection with Plasmodium parasites. Complex socioeconomic and political factors limit access to vector control and antimalarial drugs, and an estimated 600,000 people die from malaria every year. Rising drug resistance threatens to make malaria untreatable. As for all new traits, resistance is limited by fitness, and a small number of pathways are heavily favored by evolution. These pathways are targets for drug discovery. Pairing compounds active against the wild-type and the small emerging resistant population, a strategy we termed "targeting resistance," could block the rise of competitively viable resistance.
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Flaherty, Siobhan Marie. "Efficacy and Resistance Potential of JPC-3210 in Plasmodium falciparum." Scholar Commons, 2015. http://scholarcommons.usf.edu/etd/5832.
Full textAbstract:
Combating drug resistant malaria has been historically challenging, and remains so today. Recent reports from Southeast Asia show that Plasmodium falciparum is developing resistance to even our best defenses; artemisinin-based therapies. This development threatens to become a significant challenge in controlling malaria infections worldwide, making research into developing and characterizing new antimalarial drugs increasingly important. The purpose of this study was to characterize the resistance potential of novel antimalarial compound JPC-3210 in vitro using P. falciparum clones. JPC-3210 is a new long acting drug with potential to be used in combination with fast-acting drugs like artemisinins to cure drug resistant malaria. In this study several methods were used to characterize the efficacy and resistance potential of JPC-3210. To determine the frequency of resistance generation in P. falciparum clones, parasites were kept under continuous drug pressure for thirty days, at which point drug pressure was removed and cultures were observed for signs of recrudescence. P. falciparum clones also were exposed to increasing levels of intermittent drug pressure that involved 3-4 days of drug exposure followed by a recovery period. The step-wise experiment was conducted over three months with drug pressure being increased step-wise until a maximal concentration of 700 ng/ml of JPC-3210; resistance was measured phenotypically in drug susceptibility assays at multiple time points. Additionally, the ability of JPC-3210 to induce dormant stage parasites, and its effect on dihydroartemisinin (DHA)-induced dormant stages was assessed in both a chloroquine resistant parasite (W2) and in an artemisinin resistant clone (4G). Results showed that the frequency of resistance against JPC-3210 in W2 clones was less when compared to that of atovaquone. The step-wise pulse exposure of JPC-3210 induced resistance in W2 clones, however, resistance proved unstable. Dormant stage parasites were not induced by JPC-3210, even at high concentrations in W2 or 4G clones, furthermore, the effect of JPC-3210 on dormant-induced parasites was found to be dose dependent, yet the drug did not kill DHA-induced dormant rings. JPC-3210 appears to be a good drug to use in combination with other antimalarial compounds for treatment of P. falciparum, but further research is needed. Future studies to assess the field performance of new antimalarial compounds by investigating resistance and dormancy profiles in vitro, and thereby maximizing out understanding of such drugs and their optimal implementation, are of the utmost importance.
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Tacoli, Costanza. "Molecular and functional aspects of antimalarial drug resistance in isolates from Africa and Asia." Doctoral thesis, Humboldt-Universität zu Berlin, 2021. http://dx.doi.org/10.18452/22036.
Full textAbstract:
Malariakontrolle ist von Resistenzen gegen Malariamedikamente wie Chloroquin (CQ) und Artemisininderivaten (ART) bedroht. Hier untersuchten wir das Ausmaß dieser Resistenzen in Fünf Feldstudien in Nigeria, Ruanda und Südwestindien unter Beurteilung der Prävalenzen Arzneimittelresistenz-assoziierter Mutation der Plasmodium-Parasiten (P. falciparum: K13, dhps, dhfr, mdr1 und P. vivax: mdr1) z.T. in Korrelation mit klinischen Patientendaten und ex-vivo Überlebensraten (ÜLR) unter Zugabe von ART.
K13 wurde in 360 zwischen 2010-2018 gesammelte ruandischen P. falciparum Isolaten genotypisiert. Erstmals fanden wir dort niedrige Frequenzen der mit ART-Resistenz assoziierten K13-Mutation. Jedoch lassen Mutation mit niedrigen ÜLR, sowie ein Isolat mit hohen ÜLR aber ohne K13-Mutation eines Patienten der die Infektion unter Therapie nicht eliminieren konnte, Fragen offen.
Ca.100 indische P. falciparum und P. vivax Isolaten aus 2015 wurden auf Mutationen in P. falciparum Markern für die Resistenz gegen Sulfadoxin-Pyrimethamin (SP) (d.h. pfdhps/pfdhfr), Artesunat (AS) (d.h. K13) und Lumefantrin (d.h. pfmdr1) sowie P. vivax Marker für CQ-Resistenz (pvmdr1) untersucht. Der Großteil der Isolate zeigt Mutationen die SP-Resistenz hervorrufen, daher könnte die Effizienz der AS+SP-Therapie begrenzen sein. Außerdem eignet sich Lumefantrin nicht als alternatives Medikament auf Grund der beobachteten Dominanz des pfmdr1-Haplotyps „NFD“. Die Abwesenheit der pvmdr1-Mutation Y976F und erfolgreiche Behandlungen zeigen, die Wirksamkeit von CQ gegen vivax Malaria im Studiengebiet.
Auch Isolate von nigerianischen Schwangeren mit asymptomatischer P. falciparum Infektion zeigten hohe Prävalenzen von pfdhfr/pfdhps Vier- und Fünffachmutanten darum ist die Wirksamkeit der präventiver Therapie Schwangerer mit SP in Nigeria ernsthaft gefährdet.
Die Daten spiegeln die Häufigkeit der Resistenzen gegen Malariamittel in diesen Gebieten wieder mit großen Unterschieden zwischen Regionen und Medikamenten.<br>The spread of resistance to antimalarial drugs such as chloroquine (CQ) and artemisinins (ART) is a great threat to malaria control. Here, we investigated the extent of such resistance in Nigeria, Rwanda and south-western India. We assessed the prevalence of mutations in few Plasmodium parasites’ markers of resistance, namely P. falciparum genes K13 (ART), pfdhps/pfdhfr (sulfadoxine-pyrimethamine, SP) and pfmdr1 (lumefantrine) as well as P. vivax gene pvmdr1 (CQ) in 5 field studies conducted in 2010-2018, and partially correlated the results to patients’ clinical outcome. Few isolates from Rwanda, were also evaluated for their parasite ex vivo survival rates (SR) upon exposure to ART.
We tracked ART resistance in Rwanda by genotyping K13 in 360 P. falciparum isolates from 2010-2018. We showed for the first time that K13 mutations associated with ART resistance are present here, thus in Africa, at a low frequency. However, mutations occurred in patients who recovered and/or had low SR. Of note, one patient with high SR but no K13 mutation was still parasitemic after ART treatment.
Moreover, we assessed the presence of mutations in K13, pfdhps/pfdhfr, pfmdr1 and pvmdr1 in ca 100 P. falciparum and 100 P. vivax isolates from south-western India. Most of P. falciparum isolates carried pfdhfr/pfdhps mutations conferring SP resistance, menacing the efficacy of SP-ART treatment. Also, the high prevalence of pfmdr1 haplotype “NFD” advised against the introduction of lumefantrine. The low rates of P. vivax pvmdr1 Y976F and patients’ successful parasite clearance, indicated that CQ remains effective in the area.
Finally, a high rate of pfdhfr/pfdhps quadruple and quintuple mutant was observed in Nigerian pregnant women with asymptomatic P. falciparum infection, hence the effectiveness of preventive treatment with SP in pregnancy might be threatened. The data reflected the abundance of antimalarials resistance in these areas with important differences between regions and drugs.
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Aylor, Samantha Olivia. "The Effect of Drug Resistance on Plasmodium falciparum Transmission and Gametocyte Development." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4630.
Full textAbstract:
In order to reduce malaria prevalence worldwide, a better understanding of parasite transmission and the effect of drug resistance is needed. The effect of drug resistance on malaria transmission has been examined for some drugs, but not for mitochondrial inhibitors such as atovaquone and the current basis of malaria therapy, artemisinin. Therefore, the goal of this study was to produce gametocytes, the life cycle stage that transmits from mosquito to human, in several different drug resistant patient isolates as well as to determine the effect of drug resistance on gametocyte development and transmission. Previous studies have shown that the mutation that confers resistance to atovaquone, a common antimalarial, occurs de novo after treatment and transmission of this resistance is not seen in the field. Therefore, to determine whether or not the resistance mutation can be transmitted, mosquito-feeding experiments were conducted using atovaquone resistant parasites and resulting oocyst DNA was analyzed. In addition to these atovaquone studies, artemisinin resistant gametocytes were also grown in vitro and drug pressure was added to determine if resistance mechanisms affect gametocyte development. This study is the first examine gametocyte development in these resistant strains and the first to report that transmission of the atovaquone resistant mutation may be possible. However, data is currently inconclusive on the effect of artemisinin resistance on gametocyte development.
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Barclay, Victoria Charlotte. "Studies evaluating the possible evolution of malaria parasites in response to blood-stage vaccination." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/3996.
Full textAbstract:
Drug resistance is one of the most medically relevant forms of pathogen evolution. To date, vaccines have not failed with the same depressing regularity as drugs. Does that then make vaccines evolution-proof? In the face of vaccination, pathogens are thought to evolve in two ways: by evolving epitope changes at the antigenic target of vaccination (epitope evolution); or by evolving changes at other antigenic loci, some of which may involve virulence (virulence evolution). The fundamental difference between these two forms of evolution is that virulence evolution could lead to disease outcomes in unvaccinated people that are more severe than would have been seen prior to evolution. One of the theoretical assumptions of virulence evolution is that more virulent parasites will have a selective advantage over less virulent parasites in an immunized host, and are thus more likely to be transmitted. The assumption is that more virulent parasites may be competitively more superior in mixed infections, or may be better able to evade/modulate the host immune response. Thus, the aim of this thesis was to experimentally test whether more virulent parasites have a within-host selective advantage in an immunized host or whether vaccine efficacy is more likely to depend on genetic differences at the targeted sites of vaccination. I used clones (genotypes) of the rodent malaria Plasmodium chabaudi originally derived from wild-caught Thicket (Thamnomys rutilans) rats to infect laboratory mice and a rodent analogue of the candidate blood-stage malaria vaccine apical membrane antigen 1 (AMA-1). I found that within-host selection did not depend on parasite virulence, and that protective efficacy depended on genotype-specific differences at the vaccine target. Vaccine-induced protection was not enhanced by including a number of allelic variants. However, such genotype-specific responses were only observed when the vaccine was tested against genetically distinct P. chabaudi parasites. When one P. chabaudi genotype was serially passaged through naïve mice the derived line was more virulent and was subsequently less well controlled by vaccine-induced immunity. In other experiments I found within host competition not to be immune-mediated. Thus my results suggest that vaccination has the potential to select for more virulent parasites but that the selective advantage is likely to be independent of competition. The selective advantage may be attributable to the enhanced immune evasion of more virulent parasites. However, without genetic markers of virulence, the mechanisms that mediate this selection remain unknown. My thesis contributes towards a growing body of evidence that vaccines have the potential to differently alter the within-host parasite dynamics of particular pathogen genotypes and that the selection imposed is likely to be system specific, depending on the fine specificity of the vaccine-induced responses and the identity of infecting parasites. Although vaccine potency may not be enhanced by including more than one allelic variant of an antigen, multi-valent vaccines may be one of the best ways to avoid the inadvertent selection for more virulent malaria parasites.
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Yepuri, Nageshwar Rao. "The design and synthesis of novel anti-malarial agents." Access electronically, 2004. http://www.library.uow.edu.au/adt-NWU/public/adt-NWU20050330.085201/index.html.
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Carrasquilla, Manuela. "New approaches for measuring fitness of Plasmodium falciparum mutations implicated in drug resistance." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/288611.
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The repeated emergence of drug resistance in Plasmodium falciparum underscores the importance of understanding the genetic architecture of current resistance pathways, as well as any associated fitness costs. Why resistance emerges in particular regions of the world has been linked to particular genetic backgrounds that better tolerate resistance-associated polymorphisms; this is likely to play a key role in driving the epidemiology of drug resistance, however is infrequently studied at a large scale in a laboratory setting. The first results chapter establishes a barcoding approach for P. falciparum with the aim of tracking parasite growth in vitro. The strategy used was adapted for P. falciparum by using a pseudogene (PfRh3) as a safe harbour to insert unique molecular barcodes. These libraries of barcoded P. falciparum vectors were also used as a readout of transfection efficiency. The second chapter establishes a proof of principle for phenotyping by barcode sequencing, using a panel of barcoded parasites generated in different genetic backgrounds that comprise sufficient genetic diversity to pilot the method. These were grown in the presence and absence of antimalarial compounds, and growth phenotypes were measured in parallel using BarSeq. The third results chapter studies the contribution of mutations in Pfkelch13, a molecular marker of artemisinin resistance, to parasite fitness. Combining CRISPR/Cas9-based genome editing and high throughput sequencing, the impact of Pfkelch13 alleles on fitness in the context of particular strain backgrounds is revealed. In particular, the impact of genetic background in the emergence and spread of drug-resistant lineages (referred to as KEL1) in Southeast Asia carrying a Y580 Pfkelch13 allele. Overall, given the current pace of genome sequencing of pathogenic organisms such as P. falciparum, it will be important to increase the scale of experimental genetics, in order to tackle in real-time natural variation that might be under constant selection from drugs, thus anticipating the emergence of drug resistance in changing parasite populations. Through this work, tools were developed to facilitate parallel phenotyping by measuring in vitro growth using high-throughput sequencing. The work also develops novel approaches to address the importance of genetic background and a potential role for positive epistasis in a lineage responsible for the recent outbreak of drug-resistant malaria in Southeast Asia.
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Gibbons, Justin Allan. "Genomics and Transcriptomics Approaches to Understanding Drug Resistance Mechanisms in the Malaria Parasite Plasmodium falciparum." Scholar Commons, 2019. https://scholarcommons.usf.edu/etd/7794.
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The malaria parasite Plasmodium falciparum is responsible for about 500,000 deaths a year and is evolving resistance to the front-line treatment of artemisinin-based combination therapy. Resistance is currently confined to South East Asia, however millions of lives will be at risk if resistance spreads to Africa. Understanding the mechanism of resistance to artemisinins would aid containment strategies to prevent the spread of artemisinin resistance. There is also an urgent need to accelerate drug discovery since drug resistance has already been documented to all existing antimalarials. Here, I report on our efforts to understand the function of the gene k13, the gene with the strongest association with artemisinin resistance, and the potential genetic mechanisms associated with resistance to atovaquone, another widely used antimalarial.
To precisely study the transcriptome characteristics of an isogenic k13 dysregulation mutant and wild type strain, I developed a new computational algorithm called Dephasing Identifier (DI) that is capable of identifying the genes dysregulated in cell cycle shifts. DI is designed to solve the problem of pinpointing important patterns in complex genomics data with temporal sequences that cannot be resolved by standard pair-wise comparison methods, by using an innovative method that leverages external reference data for systematic comparisons. In the k13 study, I demonstrated that the algorithm identifies co- regulated gene sets that have consistent annotated functions. The DI algorithm successfully identified aberrantly early DNA replication as the driving process of transcriptome changes in the mutant.
To understand genome-wide changes that occurred in a set of atovaquone resistance stains, I analyzed whole genome sequencing data previously generated for a P. falciparum strain that underwent in vitro atovaquone selection to create atovaquone resistant strains. I systematically analyzed the genomes of these strains to search for significant genetic changes associated with atovaquone resistance; and used stringent criteria to identify genes involved in regulating transcription and protein modifications as acquiring non- synonymous mutations. Additionally, copy number variations in plasmepsin genes, a family known to be involved in resistance, were found in the resistant strains.
In summary, genomics and transcriptomics technologies can be used to rapidly identify resistance mechanisms allowing for faster adjustment of current containment strategies. Future research on the critical targets identified in this study can aid new drug discovery efforts and novel control strategies.
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Park, Daniel John. "Evolutionary Adaptation and Antimalarial Resistance in Plasmodium falciparum." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11088.
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The malaria parasite, Plasmodium falciparum, has a demonstrated history of adaptation to antimalarials and host immune pressure. This ability unraveled global eradication programs fifty years ago and seriously threatens renewed efforts today. Despite the magnitude of the global health problem, little is known about the genetic mechanisms by which the parasite evades control efforts. Population genomic methods provide a new way to identify the mutations and genes responsible for drug resistance and other clinically important traits.
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Siegel, Sasha Victoria. "Mitochondrial Heteroplasmy Contributes to the Dynamic Atovaquone Resistance Response in Plasmodium falciparum." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6586.
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Of the considerable challenges researchers face in the control and elimination of malaria, the development of antimalarial drug resistance in parasite populations remains a significant hurdle to progress worldwide. Atovaquone is used in combination with proguanil (Malarone) as an antimalarial treatment in uncomplicated malaria, but is rendered ineffective by the rapid development of atovaquone resistance during treatment. Previous studies have established that de novo mutant parasites confer resistance to atovaquone with a substitution in amino acid 268 in the cytochrome b gene encoded by the parasite mitochondrial genome, yet much is still unknown about how this resistance develops, and whether parasites are inherently predisposed to resistance development. Here we report phenotypic characterization of isolates from patients that failed treatment in the original atovaquone Phase II studies in Thailand by using a diverse series of chemotypes that target mitochondrial functions. We defined their structure-activity relationships and observed broad resistance (5-30,000 fold in atovaquone), suggesting that cytochrome b mutations alone are not sufficient to explain this spectrum of resistance. We also report the first known in vitro selection that recapitulates the clinical Y268S mutation using the TM90-C2A genetic background, the pre-treatment parent for TM90-C2B. Selection of the Y268S mutation in TM90-C2A and others indicates that the parasite genetic background is critical in the selection of clinical atovaquone resistance, since selection attempts in multiple other genetic backgrounds results in mutations at positions other than amino acid 268. We implicate mitochondrial heteroplasmy in the development of sporadic, rapid resistance to atovaquone, where pre-existing low-level mutations in the multi-copy mitochondrial DNA can be quickly selected for in parasite populations. High-coverage mitochondrial deep-sequencing data showed that low-level Y268S mutants were present in admission parasites from the atovaquone Phase II clinical trials in Thailand, and recrudescent parasites either maintained high level Y268S mutation frequencies or gradually returned to cryptic Y268S levels. The phenomenon of gradual heteroplasmic conversion back to wild-type was noted in some ex vivo patient isolated parasites as well as some in vitro selected lines, which suggests that other factors are at play that influence heteroplasmy stability. In addition to mitochondrial heteroplasmy, the total mtDNA copy number is likely influencing phenotypes in a gene dose-dependent fashion. Further, pressure on the DHODH enzyme that results in DHODH copy number amplifications/mutations has been shown to influence mitochondrial heteroplasmy directly. Last, mitochondrial diversity was shown to be vastly underestimated without heteroplasmic loci being taken into account, as seen in the re-analysis of the Pf3K MalariaGEN genome dataset we performed. The complex interactions between these drug resistance mechanisms reveal the phenotypic and genotypic plasticity that the Plasmodium falciparum parasite utilizes are a clear fitness advantage in the face of mitochondrial stress, and further studies are required to determine the impact of this wide-ranging phenotype on the development of new mitochondria-targeted drugs.
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Alker, Alisa P. Meshnick Steven R. "Molecular markers of drug resistance and clinical outcome in falciparum malaria in Cambodia and the Democratic Republic of Congo." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2006. http://dc.lib.unc.edu/u?/etd,510.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2006.<br>Title from electronic title page (viewed Oct. 10, 2007). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Epidemiology, School of Public Health." Discipline: Epidemiology; Department/School: Public Health.
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Mira, Martínez Sofía. "A new mechanism of antimalarial drug resistance regulated at the epigenetic level." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/523484.
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Malaria is responsible of almost half a million deaths every year. Currently, campaigns for the control and elimination of malaria are implemented in malaria endemic areas. However, drug resistance is one of the major impediments to achieve malaria elimination. In this thesis we have investigated how
P. falciparum parasites develop resistance to some toxic compounds by functional variation linked to epigenetic regulation of clag3 genes. These genes present clonally variant expression and determine the formation of the main channel for the transport of solutes at the membrane of the infected RBC: Plasmodium Surface Anion Channel (PSAC). Hence, we hypothesized that P. falciparum parasites can modify the permeability of the membrane to specific solutes by epigenetic regulation of clag3 genes expression; this way, parasites could develop resistance to antimalarial drugs. To test this hypothesis, we have investigated the role of switches in clag3 expression in the acquisition of resistance to the antibiotic BS, the dynamics of clag3 genes expression in human infections and we have tested drugs susceptible to failure by this drug resistance mechanism.
First, we show that BS pressure at low concentrations selected for parasites expressing clag3.1, whereas parasites exposed to higher concentrations of BS had repressed the expression of both clag3 genes. We did not find any mutation in the genome of these parasites that could explain the change in their phenotype. Thus, we concluded that parasites can develop resistance to toxic compounds through epigenetic regulation of clag3 genes. Then, we found that parasites collected from patients with uncomplicated malaria predominantly express one of the two paralogues, consistent with the property of mutually exclusive expression, previously described in lab-adapted parasite lines. Adaptation to culture conditions or selection with toxic compound results in isolate-dependent changes in clag3 expression, implying functional differences between the proteins encoded. We also observed that samples collected at day 9 post-infection in human experimental infections (when parasites had been in the peripheral blood for approximately one erythrocytic cycle) showed a mix of parasites expressing either clag3.1 or clag3.2, suggesting that the epigenetic memory of clag3 genes is reset during transmission stages. Finally, we tested whether other drugs, that are suspected to require facilitated transport to reach the cell, could be susceptible of failure by this drug resistance mechanism. We found that the antimalarial compounds T3 and T16 (bis-thiazolium salts) require the product of clag3 genes to enter the infected erythrocyte and that P. falciparum populations can develop resistance to these compounds by selection of parasites with dramatically reduced expression of both genes. The rest of the drugs that we tested might use alternative routes in which clag3 genes are not involved.
We have described for the first time an antimalarial drug resistance mechanism regulated at the epigenetic level in P. falciparum parasites. This phenomenon may be of relevance for parasite adaptation to the presence of toxic compounds in human blood, selecting rapidly those parasites that present the less permeable phenotype and developing drug resistance in a single infection.<br>Actualmente, la resistencia a los medicamentos antimaláricos es uno de los principales impedimentos para lograr la eliminación de la malaria. En esta tesis hemos investigado cómo los parásitos de P. falciparum desarrollan resistencia a algunos compuestos tóxicos por variación funcional relacionada con la regulación epigenética de los genes clag3 (clag3.1 y clag3.2), los cuales presentan expresión clonal variante y mutuamente exclusiva (en condiciones normales sólo uno de los dos genes está en estado activo). clag3 determinan la formación del canal principal para el transporte de solutos a través de la membrana del eritrocito infectado: PSAC.
En este trabajo, primero observamos que la aplicación de bajas concentraciones del antibiótico blasticidina en cultivos de P. falciparum resultó en la selección de parásitos que expresan clag3.1, mostrando una IC50 a este compuesto más elevada que aquellas líneas que expresan clag3.2. Por otro lado, parásitos expuestos a concentraciones más altas de blasticidina reprimieron la expresión de ambos clag3 y mostraron altos niveles de resistencia al fármaco. No encontramos ninguna mutación en el genoma de estos parásitos que explicase el cambio de fenotipo, sugiriendo que se trata de un mecanismo regulado a nivel epigenético. El estudio de clag3 en parásitos recolectados de pacientes con malaria no complicada mostró que P. falciparum en infecciones naturales expresa predominantemente uno de los dos parálogos: clag3.2, indicando que este patrón de expresión confiere una ventaja fenotípica en sangre humana. Por otro lado, el análisis de muestras recogidas de infecciones humanas experimentales determinó que la memoria epigenética de los genes clag3 se restablece durante las etapas de transmisión, seleccionándose en pocos ciclos aquellos parásitos que presentan el patrón de expresión más favorable en sangre humana: clag3.2. Finalmente, probamos si otros fármacos que requieren transporte facilitado para llegar a la célula podrían ser susceptibles de fracaso terapéutico a través de este mecanismo de resistencia. Hayamos que los compuestos antipalúdicos T3 y T16 (sales de bis-tiazolio) requieren el producto de los genes clag3 para ingresar en el eritrocito infectado y que poblaciones de P. falciparum puedan desarrollar resistencia a estos compuestos mediante la selección de parásitos con expresión reducida de ambos genes.
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Braun, Vera Maria [Verfasser]. "Lack of effect of intermittent preventive treatment for malaria in pregnancy and intense drug resistance in western Uganda / Vera Maria Braun." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2017. http://d-nb.info/1133074316/34.
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Beniamin, Armanos. "Establishment of an Expression and Purification System for Plasmodium falciparum Multi Drug Resistance (pfmdr) Transporter." Thesis, University of Skövde, School of Life Sciences, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-969.
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<p>Malaria is a life threatening parasite disease caused and transmitted by infected female anopheles mosquito. However, the parasite, Plasmodium falciparum, has become resistant to most anti malarial drugs, such as chloroquine, which contributes to fever and anaemia because of its ability to digest the haemoglobin in the red blood cells. The aims of this project were to establish whether “Bac to Bac” Baculoviral Expression System is suitable for expression of pfmdr 1 gene and for purification of the pgh 1 protein. The pfmdr 1 gene encodes an ABC transporter protein, pgh 1, fixed in the cell membrane of the Plasmodium falciparuum gut, which assist in elimination of drug compounds. Furthermore, “Bac to Bac” Baculoviral Expression System uses vectors with histidine tags to clone the pfmdr 1 gene and subsequently transform these into DH10Bac cells to produce the recombinant bacmid DNA. Since pfmdr 1 gene is an AT-rich sequence, PCR was optimized, by lowering the annealing and extension temperature to 47Co and 66Co respectively. The results show that “Bac to Bac” Baculoviral Expression System can be used to express the pfmdr 1 gene, though further experiments has to be performed.</p>
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Herman, Jonathan David. "Halofuginone: A Story of How Target Identification of an Ancient Chinese Medicine and Multi-Step Evolution Informs Malaria Drug Discovery." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11540.
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Malaria is a treatable communicable disease yet remains a common cause of death and disease especially among pregnant women and children. Most of malaria's worldwide burden disproportionately lies in Southeast Asia and Sub-Saharan Africa. Western medicine's 100+ year history of combating Plasmodium falciparum has taught us that the global population of malaria parasites has a unique and dangerous ability to rapidly evolve and spread drug resistance. Recently it was documented that resistance to the first-line antimalarial artemisinin may be developing in Southeast Asia.
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Villalta, Montoya Tamara. "Variation at position 86 of the pfmdr1 gene in samples from an area with seasonal transmission in eastern Sudan." Thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-111838.
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Malaria is the most common parasitic disease of humans worldwide. A factor that aggravates the many attempts to control the epidemiologic malaria situation is the spreading of resistance against anti-malarial drugs. In this project the point mutation at position 86 of the Plasmodium. falciparum multidrug resistance gene (pfmdr1), which is thought to contribute to Chloroquine resistance, was analysed in 188 samples from a low transmission area in eastern Sudan, where malaria endemicity is seasonal. The patient group studied had asymptomatic and sub patent parasitemia that persisted during the transmission-free dry season, after being treated with Chloroquine. To differentiate between wild type and mutant genotypes, nested PCR and restriction fragment length polymorphism with the enzyme Apo1 was used. Out of 188 samples 79 (42%) were successfully analysed. Of those, 72% had parasites with mutant genotypes or where mixed infection. No conclusions on the relevance of the pfmdr1 gene in the studied samples are made due to the many remaining gaps. However, eventual sources of error and previous findings in the study area are discussed.
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Jiang, Pan-Pan. "Patterns of molecular evolution and epistasis on a genomic and genic scale." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:10771.
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Epistasis describes non-additive interactions which affect gene expression and phenotype. It can happen on multiple levels, including on a genomic level with interactions between genes or even chromosomes affecting global patterns of gene expression. It can also happen within a gene itself, with epistatic interactions between amino acids affecting gene expression and resultant phenotypes. I present three studies in two organisms to study this phenomenon on a global-genomic scale, and also on a local-genic scale.
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Diallo, Diadier Amadou. "A study of the impact of insecticide-treated curtains on the prevalence of antimalarial drug resistance in children with uncomplicated malaria in Burkina Faso." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.421884.
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