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Giannangelo, Carlo, Dovile Anderson, Xiaofang Wang, Jonathan L. Vennerstrom, Susan A. Charman, and Darren J. Creek. "Ozonide Antimalarials Alkylate Heme in the Malaria Parasite Plasmodium falciparum." ACS Infectious Diseases 5, no. 12 (October 17, 2019): 2076–86. http://dx.doi.org/10.1021/acsinfecdis.9b00257.
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Dembele, Laurent, Yaw Aniweh, Nouhoum Diallo, Fanta Sogore, Cheick Papa Oumar Sangare, Aboubecrin Sedhigh Haidara, Aliou Traore, et al. "Plasmodium malariae and Plasmodium falciparum comparative susceptibility to antimalarial drugs in Mali." Journal of Antimicrobial Chemotherapy 76, no. 8 (May 22, 2021): 2079–87. http://dx.doi.org/10.1093/jac/dkab133.
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Abstract Objectives To evaluate Plasmodium malariae susceptibility to current and lead candidate antimalarial drugs. Methods We conducted cross-sectional screening and detection of all Plasmodium species malaria cases, which were nested within a longitudinal prospective study, and an ex vivo assessment of efficacy of a panel of antimalarials against P. malariae and Plasmodium falciparum, both PCR-confirmed mono-infections. Reference compounds tested included chloroquine, lumefantrine, artemether and piperaquine, while candidate antimalarials included the imidazolopiperazine GNF179, a close analogue of KAF156, and the Plasmodium phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691. Results We report a high frequency (3%–15%) of P. malariae infections with a significant reduction in ex vivo susceptibility to chloroquine, lumefantrine and artemether, which are the current frontline drugs against P. malariae infections. Unlike these compounds, potent inhibition of P. malariae and P. falciparum was observed with piperaquine exposure. Furthermore, we evaluated advanced lead antimalarial compounds. In this regard, we identified strong inhibition of P. malariae using GNF179, a close analogue of KAF156 imidazolopiperazines, which is a novel class of antimalarial drug currently in clinical Phase IIb testing. Finally, in addition to GNF179, we demonstrated that the Plasmodium PI4K-specific inhibitor KDU691 is highly inhibitory against P. malariae and P. falciparum. Conclusions Our data indicated that chloroquine, lumefantrine and artemether may not be suitable for the treatment of P. malariae infections and the potential of piperaquine, as well as new antimalarials imidazolopiperazines and PI4K-specific inhibitor, for P. malariae cure.
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Subramanian, Gowtham, Abdul Sadeer, Kalyani Mukherjee, Tadayuki Kojima, Pallavi Tripathi, Renugah Naidu, Shan Wen Tay, Jia Hao Pang, Sumod A. Pullarkat, and Rajesh Chandramohanadas. "Evaluation of ferrocenyl phosphines as potent antimalarials targeting the digestive vacuole function of Plasmodium falciparum." Dalton Transactions 48, no. 3 (2019): 1108–17. http://dx.doi.org/10.1039/c8dt04263b.
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Wicht, Kathryn J., Sachel Mok, and David A. Fidock. "Molecular Mechanisms of Drug Resistance in Plasmodium falciparum Malaria." Annual Review of Microbiology 74, no. 1 (September 8, 2020): 431–54. http://dx.doi.org/10.1146/annurev-micro-020518-115546.
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Understanding and controlling the spread of antimalarial resistance, particularly to artemisinin and its partner drugs, is a top priority. Plasmodium falciparum parasites resistant to chloroquine, amodiaquine, or piperaquine harbor mutations in the P. falciparum chloroquine resistance transporter (PfCRT), a transporter resident on the digestive vacuole membrane that in its variant forms can transport these weak-base 4-aminoquinoline drugs out of this acidic organelle, thus preventing these drugs from binding heme and inhibiting its detoxification. The structure of PfCRT, solved by cryogenic electron microscopy, shows mutations surrounding an electronegative central drug-binding cavity where they presumably interact with drugs and natural substrates to control transport. P. falciparum susceptibility to heme-binding antimalarials is also modulated by overexpression or mutations in the digestive vacuole membrane–bound ABC transporter PfMDR1 ( P. falciparum multidrug resistance 1 transporter). Artemisinin resistance is primarily mediated by mutations in P. falciparum Kelch13 protein (K13), a protein involved in multiple intracellular processes including endocytosis of hemoglobin, which is required for parasite growth and artemisinin activation. Combating drug-resistant malaria urgently requires the development of new antimalarial drugs with novel modes of action.
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Opsenica, Dejan Milos, and Bogdan Aleksandar Šolaja. "Artemisinins and synthetic peroxides as highly efficient antimalarials." Macedonian Journal of Chemistry and Chemical Engineering 31, no. 2 (December 20, 2012): 137. http://dx.doi.org/10.20450/mjcce.2012.50.
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Malaria is devastating disease and global public health problem, with nearly half world population exposed to risk. Illness is caused by five Plasmodium species, P. falciparum, P. ovale, P. vivax, P. malarie and P. knowlesi, from which P. falciparum is the most serious one causing cerebral malaria and is the major reason for malaria mortality. Vaccine against malaria is not expected in the near future and chemotherapy remains as most feasible alternative for treatment of the disease. The development of widespread drug-resistance to chloroquine (CQ), the most successful antimalarial drug up to date, has resulted in severe health issues for countries in malaria endemic regions. Organic peroxides, like artemisinins, 1,2,4-trioxanes, 1,2,4-trioxolanes, 1,2,4,5-tetraoxanes and their chimeras, are the best choice for malaria treatment nowadays. These therapeutics are fast acting, non-toxic, low costing and without reported data of parasite resistance. Stability of peroxide bonds enables synthetic comfort and resulting in diversity of synthesised structures. The most important classes of peroxide antimalarials with promising representatives are reviewed and possible mechanisms of action were presented in details.
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Miller III, Whelton A., Joshua Teye, Angela O. Achieng, Reagan M. Mogire, Hoseah Akala, John M. Ong'echa, Brijesh Rathi, Ravi Durvasula, Prakasha Kempaiah, and Samuel K. Kwofie. "Antimalarials: Review of Plasmepsins as Drug Targets and HIV Protease Inhibitors Interactions." Current Topics in Medicinal Chemistry 18, no. 23 (January 10, 2019): 2022–28. http://dx.doi.org/10.2174/1568026619666181130133548.
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Malaria is a major global health concern with the majority of cases reported in regions of South-East Asia, Eastern Mediterranean, Western Pacific, the Americas, and Sub-Saharan Africa. The World Health Organization (WHO) estimated 216 million worldwide reported cases of malaria in 2016. It is an infection of the red blood cells by parasites of the genus Plasmodium with most severe and common forms caused by Plasmodium falciparum (P. falciparum or Pf) and Plasmodium vivax (P. vivax or Pv). Emerging parasite resistance to available antimalarial drugs poses great challenges to treatment. Currently, the first line of defense includes artemisinin combination therapies (ACTs), increasingly becoming less effective and challenging to combat new occurrences of drug-resistant parasites. This necessitates the urgent need for novel antimalarials that target new molecular pathways with a different mechanism of action from the traditional antimalarials. Several new inhibitors and potential drug targets of the parasites have been reported over the years. This review focuses on the malarial aspartic proteases known as plasmepsins (Plms) as novel drug targets and antimalarials targeting Plms. It further discusses inhibitors of hemoglobin-degrading plasmepsins Plm I, Plm II, Plm IV and Histo-aspartic proteases (HAP), as well as HIV protease inhibitors of plasmepsins.
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Morales-Bayuelo, Alejandro. "New molecular target insights about protein kinases of the Plasmodium falciparum. Using molecular docking and DFT-based reactivity descriptors." Journal of Theoretical and Computational Chemistry 16, no. 08 (December 2017): 1750076. http://dx.doi.org/10.1142/s0219633617500766.
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Currently, there is increasing interest in the potential of malaria inhibitors in Plasmodium falciparum activity. In this work, is propose a possible alternative to classifying 154 antimalarials, with P. falciparum activity. These antimalarials were synthesized by the Chibale’s group ( http://www.kellychibaleresearch.uct.ac.za/ ), with the goal of finding new insights on the binding pocket of the protein kinase PfPK5, PfPK7, PfCDPK1, PfCDPK4, PfMAP1, and PfPK6 of the malaria parasite. However, there is only information about crystallography of PfPK5 and PfPK7. The protein kinases PfCDPK1, PfCDPK4, PfMAP1, and PfPK6 were modeled using molecular homology. The validation used shows that our homology models can be an alternative for the protein kinases from P. falciparum, unknown today. The antimalarials were classified by taking into account the interactions in the hinge zone. These ligands bind to the kinase through the formation of one of two hydrogen bonds, with the backbone residues of the hinge region connecting the kinase N- and C-terminal loops. These interactions were supported by a reactivity chemistry analysis, using global chemical reactivity descriptors such as chemical potential, hardness, softness, electrophilicity, and the Fukui functions as local reactivity descriptors, within the Density Functional Theory (DFT) context.
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Wilson, Danny W., Christine Langer, Christopher D. Goodman, Geoffrey I. McFadden, and James G. Beeson. "Defining the Timing of Action of Antimalarial Drugs against Plasmodium falciparum." Antimicrobial Agents and Chemotherapy 57, no. 3 (January 14, 2013): 1455–67. http://dx.doi.org/10.1128/aac.01881-12.
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ABSTRACTMost current antimalarials for treatment of clinicalPlasmodium falciparummalaria fall into two broad drug families and target the food vacuole of the trophozoite stage. No antimalarials have been shown to target the brief extracellular merozoite form of blood-stage malaria. We studied a panel of 12 drugs, 10 of which have been used extensively clinically, for their invasion, schizont rupture, and growth-inhibitory activity using high-throughput flow cytometry and new approaches for the study of merozoite invasion and early intraerythrocytic development. Not surprisingly, given reported mechanisms of action, none of the drugs inhibited merozoite invasionin vitro. Pretreatment of erythrocytes with drugs suggested that halofantrine, lumefantrine, piperaquine, amodiaquine, and mefloquine diffuse into and remain within the erythrocyte and inhibit downstream growth of parasites. Studying the inhibitory activity of the drugs on intraerythrocytic development, schizont rupture, and reinvasion enabled several different inhibitory phenotypes to be defined. All drugs inhibited parasite replication when added at ring stages, but only artesunate, artemisinin, cycloheximide, and trichostatin A appeared to have substantial activity against ring stages, whereas the other drugs acted later during intraerythrocytic development. When drugs were added to late schizonts, only artemisinin, cycloheximide, and trichostatin A were able to inhibit rupture and subsequent replication. Flow cytometry proved valuable forin vitroassays of antimalarial activity, with the free merozoite population acting as a clear marker for parasite growth inhibition. These studies have important implications for further understanding the mechanisms of action of antimalarials, studying and evaluating drug resistance, and developing new antimalarials.
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Tanaka, Takeshi Q., W. Armand Guiguemde, David S. Barnett, Maxim I. Maron, Jaeki Min, Michele C. Connelly, Praveen Kumar Suryadevara, R. Kiplin Guy, and Kim C. Williamson. "Potent Plasmodium falciparum Gametocytocidal Activity of Diaminonaphthoquinones, Lead Antimalarial Chemotypes Identified in an Antimalarial Compound Screen." Antimicrobial Agents and Chemotherapy 59, no. 3 (December 15, 2014): 1389–97. http://dx.doi.org/10.1128/aac.01930-13.
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ABSTRACTForty percent of the world's population is threatened by malaria, which is caused byPlasmodiumparasites and results in an estimated 200 million clinical cases and 650,000 deaths each year. Drug resistance has been reported for all commonly used antimalarials and has prompted screens to identify new drug candidates. However, many of these new candidates have not been evaluated against the parasite stage responsible for transmission, gametocytes. IfPlasmodium falciparumgametocytes are not eliminated, patients continue to spread malaria for weeks after asexual parasite clearance. Asymptomatic individuals can also harbor gametocyte burdens sufficient for transmission, and a safe, effective gametocytocidal agent could also be used in community-wide malaria control programs. Here, we identify 15 small molecules with nanomolar activity against late-stage gametocytes. Fourteen are diaminonaphthoquinones (DANQs), and one is a 2-imino-benzo[d]imidazole (IBI). One of the DANQs identified, SJ000030570, is a lead antimalarial candidate. In contrast, 94% of the 650 compounds tested are inactive against late-stage gametocytes. Consistent with the ineffectiveness of most approved antimalarials against gametocytes, of the 19 novel compounds with activity against known anti-asexual-stage targets, only 3 had any strong effect on gametocyte viability. These data demonstrate the distinct biology of the transmission stages and emphasize the importance of screening for gametocytocidal activity. The potent gametocytocidal activity of DANQ and IBI coupled with their efficacy against asexual parasites provides leads for the development of antimalarials with the potential to prevent both the symptoms and the spread of malaria.
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Kaddouri, Halima, Serge Nakache, Sandrine Houzé, France Mentré, and Jacques Le Bras. "Assessment of the Drug Susceptibility of Plasmodium falciparum Clinical Isolates from Africa by Using a Plasmodium Lactate Dehydrogenase Immunodetection Assay and an Inhibitory Maximum Effect Model for Precise Measurement of the 50-Percent Inhibitory Concentration." Antimicrobial Agents and Chemotherapy 50, no. 10 (October 2006): 3343–49. http://dx.doi.org/10.1128/aac.00367-06.
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ABSTRACT The extension of drug resistance among malaria-causing Plasmodium falciparum parasites in Africa necessitates implementation of new combined therapeutic strategies. Drug susceptibility phenotyping requires precise measurements. Until recently, schizont maturation and isotopic in vitro assays were the only methods available, but their use was limited by technical constraints. This explains the revived interest in the development of replacement methods, such as the Plasmodium lactate dehydrogenase (pLDH) immunodetection assay. We evaluated a commercially controlled pLDH enzyme-linked immunosorbent assay (ELISA; the ELISA-Malaria antigen test; DiaMed AG, Cressier s/Morat, Switzerland) to assess drug susceptibility in a standard in vitro assay using fairly basic laboratory equipment to study the in vitro resistance of malaria parasites to major antimalarials. Five Plasmodium falciparum clones and 121 clinical African isolates collected during 2003 and 2004 were studied by the pLDH ELISA and the [8-3H]hypoxanthine isotopic assay as a reference with four antimalarials. Nonlinear regression with a maximum effect model was used to estimate the 50% inhibitory concentration (IC50) and its confidence intervals. The two methods were observed to have similar reproducibilities, but the pLDH ELISA demonstrated a higher sensitivity. The high correlation (r = 0.98) and the high phenotypic agreement (κ = 0.88) between the two methods allowed comparison by determination of the IC50s. Recently collected Plasmodium falciparum African isolates were tested by pLDH ELISA and showed drug resistance or decreased susceptibilities of 62% to chloroquine and 11.5% to the active metabolite of amodiaquine. No decreased susceptibility to lumefantrine or the active metabolite of artemisinin was detected. The availability of this simple and highly sensitive pLDH immunodetection assay will provide an easier method for drug susceptibility testing of malaria parasites.
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Van Tyne, Daria, Alessandro D. Uboldi, Julie Healer, Alan F. Cowman, and Dyann F. Wirth. "Modulation of PF10_0355 (MSPDBL2) Alters Plasmodium falciparum Response to Antimalarial Drugs." Antimicrobial Agents and Chemotherapy 57, no. 7 (April 15, 2013): 2937–41. http://dx.doi.org/10.1128/aac.02574-12.
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ABSTRACTMalaria's ability to rapidly adapt to new drugs has allowed it to remain one of the most devastating infectious diseases of humans. Understanding and tracking the genetic basis of these adaptations are critical to the success of treatment and intervention strategies. The novel antimalarial resistance locusPF10_0355(Pfmspdbl2) was previously associated with the parasite response to halofantrine, and functional validation confirmed that overexpression of this gene lowered parasite sensitivity to both halofantrine and the structurally related antimalarials mefloquine and lumefantrine, predominantly through copy number variation. Here we further characterize the role ofPfmspdbl2in mediating the antimalarial drug response ofPlasmodium falciparum. Knockout ofPfmspdbl2increased parasite sensitivity to halofantrine, mefloquine, and lumefantrine but not to unrelated antimalarials, further suggesting that this gene mediates the parasite response to a specific class of antimalarial drugs. A single nucleotide polymorphism encoding a C591S mutation withinPfmspdbl2had the strongest association with halofantrine sensitivity and showed a high derived allele frequency among Senegalese parasites. Transgenic parasites expressing the ancestralPfmspdbl2allele were more sensitive to halofantrine and structurally related antimalarials than were parasites expressing the derived allele, revealing an allele-specific effect on drug sensitivity in the absence of copy number effects. Finally, growth competition experiments showed that under drug pressure, parasites expressing the derived allele ofPfmspdbl2outcompeted parasites expressing the ancestral allele within a few generations. Together, these experiments demonstrate that modulation ofPfmspdbl2affects malaria parasite responses to antimalarial drugs.
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Caramello, Pietro, Francesca Canta, Ilaria Cavecchia, Giuseppina Sergi, Filippo Lipani, Guido Calleri, Federico Gobbi, and Giovanni Perri. "Pharmacodynamic Analysis of Antimalarials Used in Plasmodium falciparum Imported Malaria in Northern Italy." Journal of Travel Medicine 12, no. 3 (March 8, 2006): 127–32. http://dx.doi.org/10.2310/7060.2005.12305.
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Nyamwihura, Rogers J., Huaisheng Zhang, Jasmine T. Collins, Olamide Crown, and Ifedayo Victor Ogungbe. "Nopol-Based Quinoline Derivatives as Antiplasmodial Agents." Molecules 26, no. 4 (February 14, 2021): 1008. http://dx.doi.org/10.3390/molecules26041008.
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Malaria remains a significant cause of morbidity and mortality in Sub-Saharan Africa and South Asia. While clinical antimalarials are efficacious when administered according to local guidelines, resistance to every class of antimalarials is a persistent problem. There is a constant need for new antimalarial therapeutics that complement parasite control strategies to combat malaria, especially in the tropics. In this work, nopol-based quinoline derivatives were investigated for their inhibitory activity against Plasmodium falciparum, one of the parasites that cause malaria. The nopyl-quinolin-8-yl amides (2–4) were moderately active against the asexual blood stage of chloroquine-sensitive strain Pf3D7 but inactive against chloroquine-resistant strains PfK1 and PfNF54. The nopyl-quinolin-4-yl amides and nopyl-quinolin-4-yl-acetates analogs were generally less active on all three strains. Interesting, the presence of a chloro substituent at C7 of the quinoline ring of amide 8 resulted in sub-micromolar EC50 in the PfK1 strain. However, 8 was more than two orders of magnitude less active against Pf3D7 and PfNF54. Overall, the nopyl-quinolin-8-yl amides appear to share similar antimalarial profile (asexual blood-stage) with previously reported 8-aminoquinolines like primaquine. Future work will focus on investigating the moderately active and selective nopyl-quinolin-8-yl amides on the gametocyte or liver stages of Plasmodium falciparum and Plasmodium vivax.
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Ramharter, M., H. Noedl, H. Winkler, W. Graninger, W. H. Wernsdorfer, P. G. Kremsner, and S. Winkler. "In Vitro Activity and Interaction of Clindamycin Combined with Dihydroartemisinin against Plasmodium falciparum." Antimicrobial Agents and Chemotherapy 47, no. 11 (November 2003): 3494–99. http://dx.doi.org/10.1128/aac.47.11.3494-3499.2003.
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ABSTRACT Combination regimens are considered a valuable tool for the fight against drug-resistant falciparum malaria. This study was conducted to evaluate the antimalarial potential of clindamycin in combination with dihydroartemisinin in continuously cultured and in freshly isolated Plasmodium falciparum parasites, measuring the inhibition of Plasmodium falciparum histidine-rich protein II synthesis. Interaction analysis revealed a synergistic or additive mode of interaction at various concentration ratios in all continuously cultured parasites at the 50% effective concentration (EC50) level. Antagonism was not found for any of the culture-adapted parasites. In fresh P. falciparum isolates, a fixed clindamycin-dihydroartemisinin combination exhibited additive activity at the EC50 and EC90 levels. The drug mixture showed no significant activity correlation to other commonly used antimalarials. The clindamycin-dihydroartemisinin combination appears to be a promising candidate for clinical investigation.
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Baniecki, Mary Lynn, Dyann F. Wirth, and Jon Clardy. "High-Throughput Plasmodium falciparum Growth Assay for Malaria Drug Discovery." Antimicrobial Agents and Chemotherapy 51, no. 2 (November 20, 2006): 716–23. http://dx.doi.org/10.1128/aac.01144-06.
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ABSTRACT New therapeutic agents for the treatment of malaria, the world's most deadly parasitic disease, are urgently needed. Malaria afflicts 300 to 500 million people and results in 1 to 2 million deaths annually, and more than 85% of all malaria-related mortality involves young children and pregnant women in sub-Saharan Africa. The emergence of multidrug-resistant parasites, especially in Plasmodium falciparum, has eroded the efficacy of almost all currently available therapeutic agents. The discovery of new drugs, including drugs with novel cellular targets, could be accelerated with a whole-organism high-throughput screen (HTS) of structurally diverse small-molecule libraries. The standard whole-organism screen is based on incorporation of [3H]hypoxanthine and has liabilities, such as limited throughput, high cost, multiple labor-intensive steps, and disposal of radioactive waste. Recently, screens have been reported that do not use radioactive incorporation, but their reporter signal is not robust enough for HTS. We report a P. falciparum growth assay that is technically simple, robust, and compatible with the automation necessary for HTS. The assay monitors DNA content by addition of the fluorescent dye 4′,6-diamidino-2-phenylindole (DAPI) as a reporter of blood-stage parasite growth. This DAPI P. falciparum growth assay was used to measure the 50% inhibitory concentrations (IC50s) of a diverse set of known antimalarials. The resultant IC50s compared favorably with those obtained in the [3H]hypoxanthine incorporation assay. Over 79,000 small molecules have been tested for antiplasmodial activity using the DAPI P. falciparum growth assay, and 181 small molecules were identified as highly active against multidrug-resistant parasites.
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Majeed, Muhammad Zafar, Muhammad Shahbaz Hussain, and Faiza Sarwar. "PREVALENCE OF HUMAN MALARIA." Professional Medical Journal 23, no. 06 (June 10, 2016): 655–59. http://dx.doi.org/10.29309/tpmj/2016.23.06.1602.
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Malaria is one of the devastating diseases worldwide. More than 3 billion peoplelive under the threat of malaria in endemic countries and kills more than one million each year.Malaria leads to multiple hematological (thrombocytopenia) and other abnormalities like renalsystem, nervous system with increased morbidity and mortality. Aim: The present study wasconducted to determine the prevalence of human malaria, its correlation with thrombocytopeniaand treatment in patients of District Rahim Yar Khan. Materials and Methods: A total of 200patients including 140 males and 60 females were the part of our study. Blood samples collectionwas done during September to November following monsoon season. Patients were diagnosedthrough peripheral blood smear. Both P. falciparum and P. vivax parasites against 300 white bloodcells (WBCs) were examined on the thick smear. Platelet count was done by using an automatedcell count analyzer. A platelet count of less than 150 x109/L defined thrombocytopaenia. Firstline of treatment was Chloroquine in cases of Plasmodium vivax whereas Neo fansidar incases of Plasmodium falciparum. Results: Gender wise distribution of patients was 140 (70%)males and 60(30%) females. We had 74 (37%) patients from urban and 126 (63%) from ruralpopulation. Malaria was most frequent 64% by P.vivax and 36% by P.falciparum. Fever was highduring admission to hospital and after usage of antimalarials recovery and improvement innumber of platelets was noted. Conclusion: The high prevalence rate of P. vivax pose a majorhealth hazard but of P. falciparum also may lead to serious complications. The high frequencyof human malaria infection should be a major concern for authorities in the fight against malariacontrol programs in Pakistan.
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Drinkwater, Nyssa, Komagal Kannan Sivaraman, Rebecca S. Bamert, Wioletta Rut, Khadija Mohamed, Natalie B. Vinh, Peter J. Scammells, Marcin Drag, and Sheena McGowan. "Structure and substrate fingerprint of aminopeptidase P from Plasmodium falciparum." Biochemical Journal 473, no. 19 (September 27, 2016): 3189–204. http://dx.doi.org/10.1042/bcj20160550.
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Malaria is one of the world's most prevalent parasitic diseases, with over 200 million cases annually. Alarmingly, the spread of drug-resistant parasites threatens the effectiveness of current antimalarials and has made the development of novel therapeutic strategies a global health priority. Malaria parasites have a complicated lifecycle, involving an asymptomatic ‘liver stage’ and a symptomatic ‘blood stage’. During the blood stage, the parasites utilise a proteolytic cascade to digest host hemoglobin, which produces free amino acids absolutely necessary for parasite growth and reproduction. The enzymes required for hemoglobin digestion are therefore attractive therapeutic targets. The final step of the cascade is catalyzed by several metalloaminopeptidases, including aminopeptidase P (APP). We developed a novel platform to examine the substrate fingerprint of APP from Plasmodium falciparum (PfAPP) and to show that it can catalyze the removal of any residue immediately prior to a proline. Further, we have determined the crystal structure of PfAPP and present the first examination of the 3D structure of this essential malarial enzyme. Together, these analyses provide insights into potential mechanisms of inhibition that could be used to develop novel antimalarial therapeutics.
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Tanaka, Takeshi Q., Edgar Deu, Alvaro Molina-Cruz, Michael J. Ashburne, Omar Ali, Amreena Suri, Sandhya Kortagere, Matthew Bogyo, and Kim C. Williamson. "Plasmodium Dipeptidyl Aminopeptidases as Malaria Transmission-Blocking Drug Targets." Antimicrobial Agents and Chemotherapy 57, no. 10 (July 8, 2013): 4645–52. http://dx.doi.org/10.1128/aac.02495-12.
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ABSTRACTThePlasmodium falciparumandP. bergheigenomes each contain three dipeptidyl aminopeptidase (dpap) homologs.dpap1and -3 are critical for asexual growth, but the role ofdpap2, the gametocyte-specific homolog, has not been tested. If DPAPs are essential for transmission as well as asexual growth, then a DPAP inhibitor could be used for treatment and to block transmission. To directly analyze the role of DPAP2, adpap2-minusP. berghei(Pbdpap2Δ) line was generated. ThePbdpap2Δ parasites grew normally, differentiated into gametocytes, and generated sporozoites that were infectious to mice when fed to a mosquito. However,Pbdpap1transcription was >2-fold upregulated in thePbdpap2Δ clonal lines, possibly compensating for the loss ofPbdpap2. The role of DPAP1 and -3 in thedpap2Δ parasites was then evaluated using a DPAP inhibitor, ML4118S. When ML4118S was added to thePbdpap2Δ parasites just before a mosquito membrane feed, mosquito infectivity was not affected. To assess longer exposures to ML4118S and further evaluate the role of DPAPs during gametocyte development in a parasite that causes human malaria, thedpap2deletion was repeated inP. falciparum. ViableP. falciparum dpap2(Pfdpap2)-minus parasites were obtained that produced morphologically normal gametocytes. Both wild-type andPfdpap2-negative parasites were sensitive to ML4118S, indicating that, unlike many antimalarials, ML4118S has activity against parasites at both the asexual and sexual stages and that DPAP1 and -3 may be targets for a dual-stage drug that can treat patients and block malaria transmission.
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Oyakhirome, Sunny, Saadou Issifou, Peter Pongratz, Fortune Barondi, Michael Ramharter, Jürgen F. Kun, Michel A. Missinou, Bertrand Lell, and Peter G. Kremsner. "Randomized Controlled Trial of Fosmidomycin-Clindamycin versus Sulfadoxine-Pyrimethamine in the Treatment of Plasmodium falciparum Malaria." Antimicrobial Agents and Chemotherapy 51, no. 5 (February 26, 2007): 1869–71. http://dx.doi.org/10.1128/aac.01448-06.
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ABSTRACT Fosmidomycin-clindamycin therapy given every 12 h for 3 days was compared with a standard single oral dose of sulfadoxine-pyrimethamine. The two treatments showed comparably good tolerabilities and had an identical high degree of efficacy of 94% in a randomized trial carried out with 105 Gabonese children aged 3 to 14 years with uncomplicated malaria. These antimalarials merit further clinical exploration.
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Murithi, James M., Cécile Pascal, Jade Bath, Xavier Boulenc, Nina F. Gnädig, Charisse Flerida A. Pasaje, Kelly Rubiano, et al. "The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance." Science Translational Medicine 13, no. 603 (July 21, 2021): eabg6013. http://dx.doi.org/10.1126/scitranslmed.abg6013.
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The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.
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Antia-Obong, O. E., A. A. A. Alaribe, M. U. Young, A. Bassy, and B. V. Etim. "Chloroquine-Resistant Plasmodium Falciparum Among Children in Calabar, South Eastern Nigeria." Tropical Doctor 27, no. 3 (July 1997): 146–49. http://dx.doi.org/10.1177/004947559702700309.
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Sixty-nine children aged between 6 and 60 months with parasitologically proven Plasmodium falciparum malaria were treated with chloroquine (2.5 mg/kg) in the Children's Emergency Room of the University of Calabar Teaching Hospital (UCTH) in 1993. Thirty subjects (mean age 27.8 months) and 39 (mean age 29.5 months) received chloroquine phosphate suppository (Pharma Deko) and chloroquine sulphate syrup (May & Baker), respectively. The World Health Organization (WHO) 14-day in vivo field test was used in evaluating the response to treatment. In both treatment groups the responses were similar. Overall, parasitological cure occurred in 24 subjects (34.8%) and in the remaining 45 subjects (65.2%) treatment failed (chloroquine resistance). This level of chloroquine resistant Plasmodium falciparum (CRPF) is higher than 53.6% reported in this centre in 1989. Furthermore, in the present study the proportion of RII (46.4%) is significantly higher than 21.4% ( P < 0.02) obtained in 1989. Our findings show a worsening of CRPF in Calabar with RII being the main contributor. This observation indicates the need for continued surveillance of the response of P. falciparum to chloroquine and alternative antimalarials as a means of evolving an effective treatment policy for malaria.
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Tang, Yu-Qing, Qian Ye, He Huang, and Wei-Yi Zheng. "An Overview of Available Antimalarials: Discovery, Mode of Action and Drug Resistance." Current Molecular Medicine 20, no. 8 (December 29, 2020): 583–92. http://dx.doi.org/10.2174/1566524020666200207123253.
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: Malaria is one of the three most deadly infectious diseases in the world and seriously endangers human health and life. To reduce the public health burden of this disease, scientists have focused on the discovery and development of effective antimalarial drugs, from quinine and chloroquine to antifolates and artemisinin and its derivatives, which all play a profound role in the treatment of malaria. However, drugresistant strains of Plasmodium falciparum have emerged due to frequent use of antimalarials and have become increasingly resistant to existing antimalarial drugs, causing disastrous consequences in the world. In particular, artemisinin resistance is of greatest concern which was reported in 2008. Resistance to artenisinins has been a major obstacle for malaria control, and current efforts to curb artemisinin resistance have not been successful. Based on the current situation, it is urgent to develop more effective new antimalarials with distinct targets from conventional antimalarials in the world, which could facilitate to minimize the phenomenon of drug resistance. This review aims to summarize different kinds of antimalarial therapeutic efficacy, mechanisms of action and resistance, and proposes new solutions aiming towards further improvement of malaria elimination.
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Borrmann, Steffen, Ayola A. Adegnika, Michel A. Missinou, Ronald K. Binder, Saadou Issifou, Andreas Schindler, Pierre-Blaise Matsiegui, et al. "Short-Course Artesunate Treatment of Uncomplicated Plasmodium falciparum Malaria in Gabon." Antimicrobial Agents and Chemotherapy 47, no. 3 (March 2003): 901–4. http://dx.doi.org/10.1128/aac.47.3.901-904.2003.
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ABSTRACT Artesunate is one of the most important antimalarial agents available, since it is effective against parasites that have developed resistance to conventional antimalarials in sub-Saharan Africa. Antimalarial combination chemotherapies with artesunate (4 mg/kg of body weight once daily for 3 days) as one partner have been proposed. However, the efficacy of a 3-day course of artesunate alone has never been evaluated in individuals in Africa (which has 90% of the worldwide malaria burden) living in regions of hyperendemicity, where a considerable degree of immunity might substantially enhance the efficacy of short courses of artesunate compared to those in regions where the levels of endemicity are low. This lack of information does not permit a systematic assessment of the value of artesunate-based combination chemotherapies in Africa. Therefore, we studied the efficacy and safety of a 3-day course of artesunate (4 mg/kg of body weight, orally, once daily) for the treatment of uncomplicated Plasmodium falciparum malaria in Gabonese patients aged 4 to 15 years (n = 50). Artesunate was well tolerated, and no severe adverse event was reported. Parasite elimination was rapid and was achieved in all patients within ≤72 h (geometric mean time to elimination, 34 h). The PCR-corrected cure rate by day 14 was 92% (46 of 50 patients), but it dropped to 72% (36 of 50 patients) by day 28. We conclude that a 3-day course of artesunate fails to achieve sufficiently high cure rates for uncomplicated falciparum malaria in Gabonese children.
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Frausin, Gina, Renata Braga Souza Lima, Ari de Freitas Hidalgo, Paul Maas, and Adrian Martin Pohlit. "Plants of the Annonaceae traditionally used as antimalarials: a review." Revista Brasileira de Fruticultura 36, spe1 (2014): 315–37. http://dx.doi.org/10.1590/s0100-29452014000500038.
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Species of the Annonaceae family are used all over the tropics in traditional medicine in tropical regions for the treatment of malaria and other illnesses. Phytochemical studies of this family have revealed chemical components which could offer new alternatives for the treatment and control of malaria. Searches in scientific reference sites (SciFinder Scholar, Scielo, PubMed, ScienceDirect and ISI Web of Science) and a bibliographic literature search for species of Annonaceae used traditionally to treat malaria and fever were carried out. This family contains 2,100 species in 123 genera. We encountered 113 articles reporting medicinal use of one or more species of this family including 63 species in 27 genera with uses as antimalarials and febrifuges. Even though the same species of Annonaceae are used by diverse ethnic groups, different plant parts are often chosen for applications, and diverse methods of preparation and treatment are used. The ethanol extracts of Polyalthia debilis and Xylopia aromatica proved to be quite active against Plasmodium falciparum in vitro (median inhibition concentration, IC50 < 1.5 µg/mL). Intraperitoneal injection of Annickia chlorantha aqueous extracts (cited as Enantia chlorantha) cleared chloroquine-resistant Plasmodium yoelii nigeriensis from the blood of mice in a dose-dependant manner. More phytochemical profiles of Annonaceous species are required; especially information on the more commonly distributed antimalarial compounds in this family.
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Hoppe, Heinrich C., Donelly A. van Schalkwyk, Ursula I. M. Wiehart, Sandra A. Meredith, Joanne Egan, and Brandon W. Weber. "Antimalarial Quinolines and Artemisinin Inhibit Endocytosis in Plasmodium falciparum." Antimicrobial Agents and Chemotherapy 48, no. 7 (July 2004): 2370–78. http://dx.doi.org/10.1128/aac.48.7.2370-2378.2004.
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ABSTRACT Endocytosis is a fundamental process of eukaryotic cells and fulfills numerous functions, most notably, that of macromolecular nutrient uptake. Malaria parasites invade red blood cells and during their intracellular development endocytose large amounts of host cytoplasm for digestion in a specialized lysosomal compartment, the food vacuole. In the present study we have examined the effects of artemisinin and the quinoline drugs chloroquine and mefloquine on endocytosis in Plasmodium falciparum. By using novel assays we found that mefloquine and artemisinin inhibit endocytosis of macromolecular tracers by up to 85%, while the latter drug also leads to an accumulation of undigested hemoglobin in the parasite. During 5-h incubations, chloroquine inhibited hemoglobin digestion but had no other significant effect on the endocytic pathway of the parasite, as assessed by electron microscopy, the immunofluorescence localization of hemoglobin, and the distribution of fluorescent and biotinylated dextran tracers. By contrast, when chloroquine was added to late ring stage parasites, followed by a 12-h incubation, macromolecule endocytosis was inhibited by more than 40%. Moreover, there is an accumulation of transport vesicles in the parasite cytosol, possibly due to a disruption in vacuole-vesicle fusion. This fusion block is not observed with mefloquine, artemisinin, quinine, or primaquine but is mimicked by the vacuole alkalinizing agents ammonium chloride and monensin. These results are discussed in the light of present theories regarding the mechanisms of action of the antimalarials and highlight the potential use of drugs in manipulating and studying the endocytic pathway of malaria parasites.
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Oboh, Mary Aigbiremo, Daouda Ndiaye, Hiasindh Ashmi Antony, Aida Sadikh Badiane, Upasana Shyamsunder Singh, Nazia Anwar Ali, Praveen Kumar Bharti, and Aparup Das. "Status of Artemisinin Resistance in Malaria Parasite Plasmodium falciparum from Molecular Analyses of the Kelch13 Gene in Southwestern Nigeria." BioMed Research International 2018 (October 3, 2018): 1–5. http://dx.doi.org/10.1155/2018/2305062.
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Evolution and spread of malaria parasite Plasmodium falciparum capable of evading antimalarials are the prime concern to malaria control. The currently effective drug, artemisinin (ART), is under threat due to detection of ART-resistant P. falciparum parasites in the Southeast Asian countries. It has been shown that amino acid (AA) mutations at the P. falciparum Kelch13 (Pfk13) gene provide resistance to ART. Nigeria, a part of the Sub-Saharan Africa, is highly endemic to malaria, contributing quite significantly to malaria, and resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) combination drugs has already been reported. Since artemisinin combined therapy (ACT) is the first-line drug for treatment of uncomplicated malaria in Nigeria and five amino acid mutations have been validated in the Pfk13 gene alongside with candidate mutations for ART resistance, we performed molecular surveillance for mutations (following PCR and DNA sequence analyses) in this gene from two southwestern states of Nigeria. Statistical analyses of DNA sequences were also performed following different evolutionary models. None of the different validated and candidate AA mutations of Pfk13 gene conferring resistance to ART could be detected in P. falciparum sampled in the two southwestern states of Nigeria. In addition, DNA sequencing and sequence analyses indicated neither evolutionary selection pressure on the Pfk13 gene nor association of mutations in Pfk13 gene with mutations of other three genes conferring resistance to CQ and SP. Therefore, based on the monomorphism at the Pfk13 gene and nonassociation of mutations of this gene with mutations in three other drug-resistant genes in malaria parasite P. falciparum, it can be proposed that malaria public health is not under immediate threat in southwestern Nigeria concerning ART resistance.
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van Pelt-Koops, J. C., H. E. Pett, W. Graumans, M. van der Vegte-Bolmer, G. J. van Gemert, M. Rottmann, B. K. S. Yeung, T. T. Diagana, and R. W. Sauerwein. "The Spiroindolone Drug Candidate NITD609 Potently Inhibits Gametocytogenesis and Blocks Plasmodium falciparum Transmission to Anopheles Mosquito Vector." Antimicrobial Agents and Chemotherapy 56, no. 7 (April 16, 2012): 3544–48. http://dx.doi.org/10.1128/aac.06377-11.
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ABSTRACTThe global malaria agenda has undergone a reorientation from control of clinical cases to entirely eradicating malaria. For that purpose, a key objective is blocking transmission of malaria parasites from humans to mosquito vectors. The new antimalarial drug candidate NITD609 was evaluated for its transmission-reducing potential and compared to a few established antimalarials (lumefantrine, artemether, primaquine), using a suite ofin vitroassays. By the use of a microscopic readout, NITD609 was found to inhibit the early and late development ofPlasmodium falciparumgametocytesin vitroin a dose-dependent fashion over a range of 5 to 500 nM. In addition, using the standard membrane feeding assay, NITD609 was also found to be a very effective drug in reducing transmission to theAnopheles stephensimosquito vector. Collectively, our data suggest a strong transmission-reducing effect of NITD609 acting against differentP. falciparumtransmission stages.
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McCarthy, James S., Louise Marquart, Silvana Sekuloski, Katharine Trenholme, Suzanne Elliott, Paul Griffin, Rebecca Rockett, et al. "Linking Murine and Human Plasmodium falciparum Challenge Models in a Translational Path for Antimalarial Drug Development." Antimicrobial Agents and Chemotherapy 60, no. 6 (April 4, 2016): 3669–75. http://dx.doi.org/10.1128/aac.02883-15.
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Effective progression of candidate antimalarials is dependent on optimal dosing in clinical studies, which is determined by a sound understanding of pharmacokinetics and pharmacodynamics (PK/PD). Recently, two important translational models for antimalarials have been developed: the NOD/SCID/IL2Rγ−/−(NSG) model, whereby mice are engrafted with noninfected andPlasmodium falciparum-infected human erythrocytes, and the induced blood-stage malaria (IBSM) model in human volunteers. The antimalarial mefloquine was used to directly measure the PK/PD in both models, which were compared to previously published trial data for malaria patients. The clinical part was a single-center, controlled study using a blood-stagePlasmodium falciparumchallenge inoculum in volunteers to characterize the effectiveness of mefloquine against early malaria. The study was conducted in three cohorts (n =8 each) using different doses of mefloquine. The characteristic delay in onset of action of about 24 h was seen in both NSG and IBSM systems.In vivo50% inhibitory concentrations (IC50s) were estimated at 2.0 μg/ml and 1.8 μg/ml in the NSG and IBSM models, respectively, aligning with 1.8 μg/ml reported previously for patients. In the IBSM model, the parasite reduction ratios were 157 and 195 for the 10- and 15-mg/kg doses, within the range of previously reported clinical data for patients but significantly lower than observed in the mouse model. Linking mouse and human challenge models to clinical trial data can accelerate the accrual of critical data on antimalarial drug activity. Such data can guide large clinical trials required for development of urgently needed novel antimalarial combinations. (This trial was registered at the Australian New Zealand Clinical Trials Registry [http://anzctr.org.au] under registration number ACTRN12612000323820.)
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Ducati, Rodrigo G., Hilda A. Namanja-Magliano, Rajesh K. Harijan, J. Eduardo Fajardo, Andras Fiser, Johanna P. Daily, and Vern L. Schramm. "Genetic resistance to purine nucleoside phosphorylase inhibition in Plasmodium falciparum." Proceedings of the National Academy of Sciences 115, no. 9 (February 12, 2018): 2114–19. http://dx.doi.org/10.1073/pnas.1525670115.
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Plasmodium falciparum causes the most lethal form of human malaria and is a global health concern. The parasite responds to antimalarial therapies by developing drug resistance. The continuous development of new antimalarials with novel mechanisms of action is a priority for drug combination therapies. The use of transition-state analog inhibitors to block essential steps in purine salvage has been proposed as a new antimalarial approach. Mutations that reduce transition-state analog binding are also expected to reduce the essential catalytic function of the target. We have previously reported that inhibition of host and P. falciparum purine nucleoside phosphorylase (PfPNP) by DADMe-Immucillin-G (DADMe-ImmG) causes purine starvation and parasite death in vitro and in primate infection models. P. falciparum cultured under incremental DADMe-ImmG drug pressure initially exhibited increased PfPNP gene copy number and protein expression. At increased drug pressure, additional PfPNP gene copies appeared with point mutations at catalytic site residues involved in drug binding. Mutant PfPNPs from resistant clones demonstrated reduced affinity for DADMe-ImmG, but also reduced catalytic efficiency. The catalytic defects were partially overcome by gene amplification in the region expressing PfPNP. Crystal structures of native and mutated PfPNPs demonstrate altered catalytic site contacts to DADMe-ImmG. Both point mutations and gene amplification are required to overcome purine starvation induced by DADMe-ImmG. Resistance developed slowly, over 136 generations (2136 clonal selection). Transition-state analog inhibitors against PfPNP are slow to induce resistance and may have promise in malaria therapy.
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Ling, Liqin, Maruthi Mulaka, Justin Munro, Swati Dass, Michael W. Mather, Michael K. Riscoe, Manuel Llinás, Jing Zhou, and Hangjun Ke. "Genetic ablation of the mitoribosome in the malaria parasite Plasmodium falciparum sensitizes it to antimalarials that target mitochondrial functions." Journal of Biological Chemistry 295, no. 21 (April 9, 2020): 7235–48. http://dx.doi.org/10.1074/jbc.ra120.012646.
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The mitochondrion of malaria parasites contains several clinically validated drug targets. Within Plasmodium spp., the causative agents of malaria, the mitochondrial DNA (mtDNA) is only 6 kb long, being the smallest mitochondrial genome among all eukaryotes. The mtDNA encodes only three proteins of the mitochondrial electron transport chain and ∼27 small, fragmented rRNA genes having lengths of 22–195 nucleotides. The rRNA fragments are thought to form a mitochondrial ribosome (mitoribosome), together with ribosomal proteins imported from the cytosol. The mitoribosome of Plasmodium falciparum is essential for maintenance of the mitochondrial membrane potential and parasite viability. However, the role of the mitoribosome in sustaining the metabolic status of the parasite mitochondrion remains unclear. The small ribosomal subunit in P. falciparum has 14 annotated mitoribosomal proteins, and employing a CRISPR/Cas9-based conditional knockdown tool, here we verified the location and tested the essentiality of three candidates (PfmtRPS12, PfmtRPS17, and PfmtRPS18). Using immuno-EM, we provide evidence that the P. falciparum mitoribosome is closely associated with the mitochondrial inner membrane. Upon knockdown of the mitoribosome, parasites became hypersensitive to inhibitors targeting mitochondrial Complex III (bc1), dihydroorotate dehydrogenase (DHOD), and the F1F0-ATP synthase complex. Furthermore, the mitoribosome knockdown blocked the pyrimidine biosynthesis pathway and reduced the cellular pool of pyrimidine nucleotides. These results suggest that disruption of the P. falciparum mitoribosome compromises the metabolic capacity of the mitochondrion, rendering the parasite hypersensitive to a panel of inhibitors that target mitochondrial functions.
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Gadalla, Nahla B., Ishag Adam, Salah-Eldin Elzaki, Sahar Bashir, Izdihar Mukhtar, Mary Oguike, Amal Gadalla, et al. "Increasedpfmdr1Copy Number and Sequence Polymorphisms in Plasmodium falciparum Isolates from Sudanese Malaria Patients Treated with Artemether-Lumefantrine." Antimicrobial Agents and Chemotherapy 55, no. 11 (September 6, 2011): 5408–11. http://dx.doi.org/10.1128/aac.05102-11.
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ABSTRACTMolecular markers for surveillance ofPlasmodium falciparumresistance to current antimalarials are sorely needed. A 28-day efficacy study of artemether-lumefantrine in eastern Sudan identified 5 treatment failures among 100 evaluable patients; 9 further individuals were parasite positive by PCR during follow-up. Polymorphisms inpfatpase6andpfmdr1were evaluated by DNA sequencing. One individual carried parasites with a novelpfmdr1polymorphism (F1044L).pfmdr1gene amplification in parasites prior to treatment occurred in three individuals who had recurrent infection during follow-up.
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Songsungthong, Warangkhana, Supasak Kulawonganunchai, Alisa Wilantho, Sissades Tongsima, Pongpisid Koonyosying, Chairat Uthaipibull, Sumalee Kamchonwongpaisan, and Philip J. Shaw. "The Plasmodium berghei RC strain is highly diverged and harbors putatively novel drug resistance variants." PeerJ 5 (October 5, 2017): e3766. http://dx.doi.org/10.7717/peerj.3766.
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Background The current first line drugs for treating uncomplicated malaria are artemisinin (ART) combination therapies. However, Plasmodium falciparum parasites resistant to ART and partner drugs are spreading, which threatens malaria control efforts. Rodent malaria species are useful models for understanding antimalarial resistance, in particular genetic variants responsible for cross resistance to different compounds. Methods The Plasmodium berghei RC strain (PbRC) is described as resistant to different antimalarials, including chloroquine (CQ) and ART. In an attempt to identify the genetic basis for the antimalarial resistance trait in PbRC, its genome was sequenced and compared with five other previously sequenced P. berghei strains. Results We found that PbRC is eight-fold less sensitive to the ART derivative artesunate than the reference strain PbANKA. The genome of PbRC is markedly different from other strains, and 6,974 single nucleotide variants private to PbRC were identified. Among these PbRC private variants, non-synonymous changes were identified in genes known to modulate antimalarial sensitivity in rodent malaria species, including notably the ubiquitin carboxyl-terminal hydrolase 1 gene. However, no variants were found in some genes with strong evidence of association with ART resistance in P. falciparum such as K13 propeller protein. Discussion The variants identified in PbRC provide insight into P. berghei genome diversity and genetic factors that could modulate CQ and ART resistance in Plasmodium spp.
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Biddau, Marco, and Lilach Sheiner. "Targeting the apicoplast in malaria." Biochemical Society Transactions 47, no. 4 (August 5, 2019): 973–83. http://dx.doi.org/10.1042/bst20170563.
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Abstract Malaria continues to be one of the leading causes of human mortality in the world, and the therapies available are insufficient for eradication. Severe malaria is caused by the apicomplexan parasite Plasmodium falciparum. Apicomplexan parasites, including the Plasmodium spp., are descendants of photosynthetic algae, and therefore they possess an essential plastid organelle, named the apicoplast. Since humans and animals have no plastids, the apicoplast is an attractive target for drug development. Indeed, after its discovery, the apicoplast was found to host the target pathways of some known antimalarial drugs, which motivated efforts for further research into its biological functions and biogenesis. Initially, many apicoplast inhibitions were found to result in ‘delayed death’, whereby parasite killing is seen only at the end of one invasion-egress cycle. This slow action is not in line with the current standard for antimalarials, which seeded scepticism about the potential of compounds targeting apicoplast functions as good candidates for drug development. Intriguingly, recent evidence of apicoplast inhibitors causing rapid killing could put this organelle back in the spotlight. We provide an overview of drugs known to inhibit apicoplast pathways, alongside recent findings in apicoplast biology that may provide new avenues for drug development.
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Duez, Julien, John P. Holleran, Papa Alioune Ndour, Sasdekumar Loganathan, Pascal Amireault, Olivier Français, Wassim El Nemer, et al. "Splenic Retention of Plasmodium falciparum Gametocytes To Block the Transmission of Malaria." Antimicrobial Agents and Chemotherapy 59, no. 7 (May 4, 2015): 4206–14. http://dx.doi.org/10.1128/aac.05030-14.
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ABSTRACTPlasmodium falciparumis transmitted from humans toAnophelesmosquito vectors via the sexual erythrocytic forms termed gametocytes. Erythrocyte filtration through microsphere layers (microsphiltration) had shown that circulating gametocytes are deformable. Compounds reducing gametocyte deformability would induce their splenic clearance, thus removing them from the blood circulation and blocking malaria transmission. The hand-made, single-sample prototype for microsphiltration was miniaturized to a 96-well microtiter plate format, and gametocyte retention in the microsphere filters was quantified by high-content imaging. The stiffening activity of 40 pharmacological compounds was assessed in microtiter plates, using a small molecule (calyculin) as a positive control. The stiffening activity of calyculin was assessed in spleen-mimetic microfluidic chips and in macrophage-depleted mice. Marked mechanical retention (80% to 90%) of mature gametocytes was obtained in microplates following exposure to calyculin at concentrations with no effect on parasite viability. Of the 40 compounds tested, including 20 antimalarials, only 5 endoperoxides significantly increased gametocyte retention (1.5- to 2.5-fold; 24 h of exposure at 1 μM). Mature gametocytes exposed to calyculin accumulated in microfluidic chips and were cleared from the circulation of macrophage-depleted mice as rapidly as heat-stiffened erythrocytes, thus confirming results obtained using the microsphiltration assay. An automated miniaturized approach to select compounds for their gametocyte-stiffening effect has been established. Stiffening induces gametocyte clearance bothin vitroandin vivo. Based on physiologically validated tools, this screening cascade can identify novel compounds and uncover new targets to block malaria transmission. Innovative applications in hematology are also envisioned.
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Rodrigues Henriques, Juan Ricardo, and Neira Gamboa de Domínguez. "Modulation of the oxidative stress in malaria infection by clotrimazole." Brazilian Journal of Pharmaceutical Sciences 48, no. 3 (September 2012): 519–28. http://dx.doi.org/10.1590/s1984-82502012000300019.
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Antimycotic clotrimazole (CTZ) has demonstrated remarkable activity against Plasmodium falciparum in vitro and in vivo. Hemoglobin degradation by Plasmodium parasites makes amino acids available for protein synthesis, inducing oxidative stress in infected cells and producing free heme. These events represent biochemical targets for potential antimalarials. In this study, we have tested the ability of CTZ to modify the oxidative status in Plasmodium berghei-infected erythrocytes. After hemolysis, activities of superoxide dismutase (SOD), catalase (CAT), glutathione cycle and NADPH+H+-producing dehydrogenases were investigated using UV-visible spectrophotometry. Thiobarbituric acid reactive substances (TBARS) were evaluated as a marker of lipid damage. Results showed that CTZ significantly decreased the overall activity of 6-phosphagluconate dehydrogenase (6PGD) compared to infected and non-treated cells; consequently, the glutathione cycle was inhibited, leaving the parasite vulnerable to the oxidative stress originating from hemoglobin degradation. As a compensatory response, CTZ prevented some loss of SOD and CAT activities in infected cells. The infection triggered lipid peroxidation in erythrocytes, which was decreased by CTZ. These results suggest the presence of a redox unbalance in cells treated with CTZ, discussing a possible effect of this compound disturbing the oxidative status in a Plasmodium berghei-infection.
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Locher, Christopher P., Peter C. Ruben, Jiri Gut, and Philip J. Rosenthal. "5HT1A Serotonin Receptor Agonists Inhibit Plasmodium falciparum by Blocking a Membrane Channel." Antimicrobial Agents and Chemotherapy 47, no. 12 (December 2003): 3806–9. http://dx.doi.org/10.1128/aac.47.12.3806-3809.2003.
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ABSTRACT Toidentify new leads for the treatment of Plasmodium falciparum malaria, we screened a panel of serotonin (5-hydroxytryptamine [5HT]) receptor agonists and antagonists and determined their effects on parasite growth. The 5HT1A receptor agonists 8-hydroxy-N-(di-n-propyl)-aminotetralin (8-OH-DPAT), 2,5-dimethoxy-4-iodoamphetamine, and 2,5-dimethoxy-4-bromophenylethylamine inhibited the growth of P. falciparum in vitro (50% inhibitory concentrations, 0.4, 0.7, and 1.5 μM, respectively). In further characterizing the antiparasitic effects of 8-OH-DPAT, we found that this serotonin receptor agonist did not affect the growth of Leishmania infantum, Trypanosoma cruzi, Trypanosoma brucei brucei, or Trichostrongylus colubriformis in vitro and did not demonstrate cytotoxicity against the human lung fibroblast cell line MRC-5. 8-OH-DPAT had similar levels of growth inhibition against several different P. falciparum isolates having distinct chemotherapeutic resistance phenotypes, and its antimalarial effect was additive when it was used in combination with chloroquine against a chloroquine-resistant isolate. In a patch clamp assay, 8-OH-DPAT blocked a P. falciparum surface membrane channel, suggesting that serotonin receptor agonists are a novel class of antimalarials that target a nutrient transport pathway. Since there may be neurological involvement with the use of 8-OH-DPAT and other serotonin receptor agonists in the treatment of falciparum malaria, new lead compounds derived from 8-OH-DPAT will need to be modified to prevent potential neurological side effects. Nevertheless, these results suggest that 8-OH-DPAT is a new lead compound with which to derive novel antimalarial agents and is a useful tool with which to characterize P. falciparum membrane channels.
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Khim, Nimol, Christiane Bouchier, Marie-Thérèse Ekala, Sandra Incardona, Pharath Lim, Eric Legrand, Ronan Jambou, Socheat Doung, Odile Mercereau Puijalon, and Thierry Fandeur. "Countrywide Survey Shows Very High Prevalence of Plasmodium falciparum Multilocus Resistance Genotypes in Cambodia." Antimicrobial Agents and Chemotherapy 49, no. 8 (August 2005): 3147–52. http://dx.doi.org/10.1128/aac.49.8.3147-3152.2005.
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ABSTRACT Cambodia is located in an area of resistance to multiple antimalarials and has been the first country to implement the systematic use of an artesunate-mefloquine combination as first-line treatment for Plasmodium falciparum malaria. Little is known, however, about the prevalence of resistance mutations within the natural parasite populations, impeding rational drug policy in this context. Using direct sequencing of PCR products, we have analyzed sequence polymorphism of the dihydrofolate reductase-thymidylate synthase, dihydropteroate synthetase, and multidrug resistance 1 genes in a large number of clinical P. falciparum isolates collected in various areas of Cambodia. This highlighted a 100% prevalence of haplotypes with multiple mutations in the target genes of antifolates after more than a decade without use of antifolates for malaria therapy. A high prevalence of mutations in Pfmdr1, including mutations associated with decreased in vitro susceptibility to mefloquine and quinine, was also observed. In addition, novel, low-frequency mutations were detected in Pfmdr1. Our findings show an alarming rate of multilocus resistance genotypes in Cambodia, requiring diligent surveillance and imposing limitations on possible future drug combinations.
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Heppner, DG, PE Hallaway, GJ Kontoghiorghes, and JW Eaton. "Antimalarial properties of orally active iron chelators." Blood 72, no. 1 (July 1, 1988): 358–61. http://dx.doi.org/10.1182/blood.v72.1.358.358.
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Abstract The appearance of widespread multiple drug resistance in human malaria has intensified the search for new antimalarial compounds. Metal chelators, especially those with high affinity for iron, represent one presently unexploited class of antimalarials. Unfortunately the use of previously identified chelators as antimalarials has been precluded by their toxicity and, in the case of desferrioxamine, the necessity for parenteral administration. The investigators now report that a new class of orally active iron chelators, namely the derivatives of alpha- ketohydroxypyridines (KHPs), are potent antimalarials against cultured Plasmodium falciparum. The KHPs evidently exert this effect by sequestering iron because a preformed chelator:iron complex has no antimalarial action. The pool(s) of iron being sequestered by the chelators have not been identified but may not include serum transferrin. Preincubation of human serum with KHPs followed by removal of the drug results in the removal of greater than 97% of total serum iron. Nonetheless, this serum effectively supports the growth of P falciparum cultures. Therefore the KHPs may exert antimalarial effect through chelation of erythrocytic rather than serum iron pool(s). The investigators conclude that these powerful, orally active iron chelators may form the basis of a new class of antimalarial drugs.
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Heppner, DG, PE Hallaway, GJ Kontoghiorghes, and JW Eaton. "Antimalarial properties of orally active iron chelators." Blood 72, no. 1 (July 1, 1988): 358–61. http://dx.doi.org/10.1182/blood.v72.1.358.bloodjournal721358.
Full textAbstract:
The appearance of widespread multiple drug resistance in human malaria has intensified the search for new antimalarial compounds. Metal chelators, especially those with high affinity for iron, represent one presently unexploited class of antimalarials. Unfortunately the use of previously identified chelators as antimalarials has been precluded by their toxicity and, in the case of desferrioxamine, the necessity for parenteral administration. The investigators now report that a new class of orally active iron chelators, namely the derivatives of alpha- ketohydroxypyridines (KHPs), are potent antimalarials against cultured Plasmodium falciparum. The KHPs evidently exert this effect by sequestering iron because a preformed chelator:iron complex has no antimalarial action. The pool(s) of iron being sequestered by the chelators have not been identified but may not include serum transferrin. Preincubation of human serum with KHPs followed by removal of the drug results in the removal of greater than 97% of total serum iron. Nonetheless, this serum effectively supports the growth of P falciparum cultures. Therefore the KHPs may exert antimalarial effect through chelation of erythrocytic rather than serum iron pool(s). The investigators conclude that these powerful, orally active iron chelators may form the basis of a new class of antimalarial drugs.
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Sharma, Shilpi, Shailendra Kumar Sharma, Rahul Modak, Krishanpal Karmodiya, Namita Surolia, and Avadhesha Surolia. "Mass Spectrometry-Based Systems Approach for Identification of Inhibitors of Plasmodium falciparum Fatty Acid Synthase." Antimicrobial Agents and Chemotherapy 51, no. 7 (May 7, 2007): 2552–58. http://dx.doi.org/10.1128/aac.00124-07.
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ABSTRACT The emergence of strains of Plasmodium falciparum resistant to the commonly used antimalarials warrants the development of new antimalarial agents. The discovery of type II fatty acid synthase (FAS) in Plasmodium distinct from the FAS in its human host (type I FAS) opened up new avenues for the development of novel antimalarials. The process of fatty acid synthesis takes place by iterative elongation of butyryl-acyl carrier protein (butyryl-ACP) by two carbon units, with the successive action of four enzymes constituting the elongation module of FAS until the desired acyl length is obtained. The study of the fatty acid synthesis machinery of the parasite inside the red blood cell culture has always been a challenging task. Here, we report the in vitro reconstitution of the elongation module of the FAS of malaria parasite involving all four enzymes, FabB/F (β-ketoacyl-ACP synthase), FabG (β-ketoacyl-ACP reductase), FabZ (β-ketoacyl-ACP dehydratase), and FabI (enoyl-ACP reductase), and its analysis by matrix-assisted laser desorption-time of flight mass spectrometry (MALDI-TOF MS). That this in vitro systems approach completely mimics the in vivo machinery is confirmed by the distribution of acyl products. Using known inhibitors of the enzymes of the elongation module, cerulenin, triclosan, NAS-21/91, and (−)-catechin gallate, we demonstrate that accumulation of intermediates resulting from the inhibition of any of the enzymes can be unambiguously followed by MALDI-TOF MS. Thus, this work not only offers a powerful tool for easier and faster throughput screening of inhibitors but also allows for the study of the biochemical properties of the FAS pathway of the malaria parasite.
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SEGURADO, Aluisio Augusto Cotrim, Silvia Maria DI SANTI, and Mario SHIROMA. "In vivo and in vitro Plasmodium falciparum Resistance to Chloroquine, Amodiaquine and Quinine in the Brazilian Amazon." Revista do Instituto de Medicina Tropical de São Paulo 39, no. 2 (March 1997): 85–90. http://dx.doi.org/10.1590/s0036-46651997000200004.
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In order to study the chemoresistance of Plasmodium falciparum to commonly used antimalarial drugs in Brazil the authors have studied ten patients with falciparum malaria, acquired in the Brazilian Amazon region. Patients were submitted to in vivo study of drug sensitivity, after chemotherapy with either 4-aminoquinolines (chloroquine or amodiaquine) or quinine. Adequate drug absorption was confirmed by standard urine excretion tests for antimalarials. Eight patients could be followed up to 28 days. Among these in vivo resistance (R I and R II responses) was seen in all patients who received 4-amino-quinolines. One patient treated with quinine exhibited a R III response. Peripheral blood samples of the same patients were submitted to in vitro microtests for sensitivity to antimalarials. Out of nine successful tests, resistance to chloroquine and amodiaquine was found in 100% and resistance to quinine in 11.11% of isolates. Probit analysis of log dose-response was used to determine effective concentrations EC50, EC90 and EC99 to the studied drugs. Good correlation between in vivo and in vitro results was seen in six patients. The results emphasize high levels of P. falciparum resistance to 4- aminoquinolines and suggest an increase in resistance to quinine in the Brazilian Amazon region, reinforcing the need for continuous monitoring of drug sensitivity to adequate chemotherapy according to the most efficacious drug regimens
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Choudhary, Amit, Manish Sinha, Arti Devi, Shammy Jindal, and Kamya Goyal. "A Review on Antimalarial 1,2,4-Trioxane Derivatives." Journal of Drug Delivery and Therapeutics 10, no. 4-s (August 15, 2020): 240–53. http://dx.doi.org/10.22270/jddt.v10i4-s.4268.
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Malaria in recent years becomes a major health hitch globally due to the surfacing of multidrug-resistant strains of Plasmodium falciparum parasite. In recent times, artemisinin (ART)-based drugs and combination therapies become the drugs of preference for the treatment and prophylaxis of resistant P. falciparum malaria. Endoperoxide compounds natural, semi-synthetic or synthetic signifying a massive number of antimalarial agents which possess a wide structural miscellany with needed antimalarial effectiveness against resistant P. falciparum malaria. The 1,2,4-trioxane ring system deficient the lactone ring which constitutes the most significant endoperoxide structural scaffold which is believed to be the key pharmacophoric moiety and is principally responsible for the pharmacodynamic potential of endoperoxide-based antimalarials. This becomes the main reason for the research related to endoperoxide particularly 1,2,4-trioxane-, 1,2,4-trioxolane- and 1,2,4,5-tetraoxane-based scaffolds gaining the noteworthy interest in recent years for developing antimalarial drugs against resistant malaria. In this paper, a comprehensive endeavour has been made to review the development of different endoperoxide antimalarial agents and structural diversity of endoperoxide molecules derived from 1,2,4-trioxane- based structural scaffolds.
Keywords: Endoperoxide; 1,2,4-trioxane; pharmacophores; artemisinin; antimalarial.
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Crandall, Ian, Jeffrey Charuk, and Kevin C. Kain. "Nonylphenolethoxylates as Malarial Chloroquine Resistance Reversal Agents." Antimicrobial Agents and Chemotherapy 44, no. 9 (September 1, 2000): 2431–34. http://dx.doi.org/10.1128/aac.44.9.2431-2434.2000.
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ABSTRACT Malaria-associated morbidity and mortality are increasing because of widespread resistance to one of the safest and least expensive antimalarials, chloroquine. The availability of an inexpensive agent that is capable of reversing chloroquine resistance would have a major impact on malaria treatment worldwide. The interaction of nonylphenolethoxylates (NPEs, commercially available synthetic surfactants) with drug-resistant Plasmodium falciparum was examined to determine if NPEs inhibited the growth of the parasites and if NPEs could sensitize resistant parasites to chloroquine. NPEs inhibited the development of the parasite when present in the low- to mid-micromolar range (5 to 90 μM), indicating that they possess antimalarial activity. Further, the presence of <10 μM concentrations of NPEs caused the 50% inhibitory concentrations for chloroquine-resistant lines to drop to levels (≤12 nM) observed for sensitive lines and generally considered to be achievable with treatment courses of chloroquine. Long-chain (>30 ethoxylate units) NPEs were found to be most active in P. falciparum, which contrasts with previously observed maximal activity of short-chain (∼9 ethoxylate units) NPEs in multidrug-resistant mammalian cell lines. NPEs may be attractive chloroquine resistance reversal agents since they are inexpensive and may be selectively directed againstP. falciparum without inhibiting mammalian tissue P glycoproteins. Antimalarial preparations that include these agents may prolong the effective life span of chloroquine and other antimalarials.
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Chhim, Srean, Patrice Piola, Tambri Housen, Vincent Herbreteau, and Bunkea Tol. "Malaria in Cambodia: A Retrospective Analysis of a Changing Epidemiology 2006–2019." International Journal of Environmental Research and Public Health 18, no. 4 (February 18, 2021): 1960. http://dx.doi.org/10.3390/ijerph18041960.
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Background: In Cambodia, malaria persists with changing epidemiology and resistance to antimalarials. This study aimed to describe how malaria has evolved spatially from 2006 to 2019 in Cambodia. Methods: We undertook a secondary analysis of existing malaria data from all government healthcare facilities in Cambodia. The epidemiology of malaria was described by sex, age, seasonality, and species. Spatial clusters at the district level were identified with a Poisson model. Results: Overall, incidence decreased from 7.4 cases/1000 population in 2006 to 1.9 in 2019. The decrease has been drastic for females, from 6.7 to 0.6/1000. Adults aged 15–49 years had the highest malaria incidence among all age groups. The proportion of Plasmodium (P.) falciparum + Mixed among confirmed cases declined from 87.9% (n = 67,489) in 2006 to 16.6% (n = 5290) in 2019. Clusters of P. falciparum + Mixed and P. vivax + Mixed were detected in forested provinces along all national borders. Conclusions: There has been a noted decrease in P. falciparum cases in 2019, suggesting that an intensification plan should be maintained. A decline in P. vivax cases was also noted, although less pronounced. Interventions aimed at preventing new infections of P. vivax and relapses should be prioritized. All detected malaria cases should be captured by the national surveillance system to avoid misleading trends.
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Parkinson, Christopher J., Geoffrey W. Birrell, Marina Chavchich, Donna Mackenzie, Richard K. Haynes, Carmen de Kock, Des R. Richardson, and Michael D. Edstein. "Development of pyridyl thiosemicarbazones as highly potent agents for the treatment of malaria after oral administration." Journal of Antimicrobial Chemotherapy 74, no. 10 (July 19, 2019): 2965–73. http://dx.doi.org/10.1093/jac/dkz290.
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AbstractObjectivesDrug resistance exists to all current and investigational antimalarial drug classes. Consequently, we have set out to develop chemically and mechanistically discrete antimalarials. Here we report on the development of thiosemicarbazone (TSC) antimalarials, with TSC3 as the most advanced lead.MethodsThiosemicarbazones were generated through simple condensation reactions of thiosemicarbazides and ketones. TSC3 was selected and tested for in vitro antimalarial activities against MDR Plasmodium falciparum lines using the [3H]hypoxanthine growth assay, in vitro cytotoxicity against mammalian cell lines using the alamarBlue fluorescence cell viability assay, in vivo potency in the mouse–Plasmodium berghei model and blood exposure in mice measured by LC-MS for pharmacokinetic analysis.ResultsTSC3 showed potent in vitro activity against atovaquone-, dihydroartemisinin-, chloroquine- and mefloquine-resistant P. falciparum lines (EC50 <15 nM). The selectivity index (EC50 cells/EC50Pf W2 line) of TSC3 was >500 in two of three mammalian cell lines. In P. berghei-infected mice, TSC3 showed potent activity in the Peters 4 day suppression test (ED50 1.2 mg/kg/day) and was as potent as artesunate and chloroquine in the curative modified Thompson test. A single oral dose of TSC3 at 16 mg/kg in healthy mice achieved a mean maximum blood concentration of 1883 ng/mL at 1 h after dosing and an elimination half-life of 48.7 h in groups of five mice.ConclusionsTSC3 shows promise as a persistent, potent and orally effective antimalarial. This, coupled with the extremely low cost of synthesis, suggests that the further development of antimalarial thiosemicarbazones is clearly warranted.
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Morozova, L. F., A. V. Kondrashin, E. V. Stepanova, V. P. Sergiev, M. S. Maksimova, N. A. Turbabina, N. S. Malysheva, E. A. Solovyeva, I. V. Kurashkina, and E. N. Morozov. "In vivo effectiveness of the inhibitors of telomerase against malaria parasites." Infekcionnye bolezni 18, no. 4 (2020): 127–32. http://dx.doi.org/10.20953/1729-9225-2020-4-127-132.
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One of the most dangerous causative agents of malaria is Plasmodium falciparum, transmitted by various Anopheline mosquitoes. Due to widespread drug resistance to practically all antimalarials, novel and effective drugs to manage this important disease are urgently required. In this study we evaluated the antimalarial activity of a series of 14 compounds from the inhibitors of the telomerase group. For in vivo studies we used P. berghei strain NK 65 in white unbread mice. The most antimalarial activity was shown by Imatinib, Phosphazide and Imetelstat. We found that Imatinib is the most potent compound and therefore can serve as a potential lead for the development of new antimalarial drug. Key words: malaria, drug resistance, inhibitors of telomerase, imatinib, chemotherapy of malaria
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Akompong, Thomas, Saliha Eksi, Kim Williamson, and Kasturi Haldar. "Gametocytocidal Activity and Synergistic Interactions of Riboflavin with Standard Antimalarial Drugs against Growth of Plasmodium falciparum In Vitro." Antimicrobial Agents and Chemotherapy 44, no. 11 (November 1, 2000): 3107–11. http://dx.doi.org/10.1128/aac.44.11.3107-3111.2000.
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ABSTRACT Our previous studies have shown that riboflavin has activity against Plasmodium falciparum asexual-stage parasites in vitro. In the present study we examine the gametocytocidal activity of riboflavin and the interaction of riboflavin with some commonly used antimalarial drugs against the asexual forms of P. falciparum in vitro. The addition of riboflavin to P. falciparum cultures killed gametocytes at all stages, even those at late stages (III to V), which are not affected by many of the commonly used antimalarials. Combinations of riboflavin with mefloquine, pyrimethamine, and quinine showed a marked potentiation of the activities of these drugs against asexual-stage parasites in vitro. The combination of riboflavin with artemisinin was additive, while that with chloroquine was mildly antagonistic. High doses of riboflavin are used clinically to treat several inborn errors of metabolism with no adverse side effects. Its efficacy in combination with standard antimalarial drugs in treating and preventing the transmission ofP. falciparum malaria can therefore be evaluated in humans.
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Peters, W. "The problem of drug resistance in malaria." Parasitology 90, no. 4 (April 1985): 705–15. http://dx.doi.org/10.1017/s003118200005232x.
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The resistance in human malaria is mainly of practical importance in relation to Plasmodium falciparum. Strains resistant not only to chloroquine but also to dihydrofolate reductase inhibitors, and even to potentiating combinations of these with sulphonamides or sulphones, are appearing in an ever increasing geographical area which now includes tropical Africa and India. Few new drugs are available or foreseen for the near future, mefloquine and artemisinine being the leading contenders. It is vital that all measures possible should be taken to protect such new compounds, their deployment in the form of judiciously selected combinations with other antimalarials being an essential procedure that should be followed. Drugs in new chemical classes and with different modes of action are still urgently needed. Reliance should not be placed on drugs alone to control malaria on a community basis.
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Lucumi, Edinson, Claire Darling, Hyunil Jo, Andrew D. Napper, Rajesh Chandramohanadas, Nicholas Fisher, Alison E. Shone, et al. "Discovery of Potent Small-Molecule Inhibitors of Multidrug-Resistant Plasmodium falciparum Using a Novel Miniaturized High-Throughput Luciferase-Based Assay." Antimicrobial Agents and Chemotherapy 54, no. 9 (June 14, 2010): 3597–604. http://dx.doi.org/10.1128/aac.00431-10.
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ABSTRACT Malaria is a global health problem that causes significant mortality and morbidity, with more than 1 million deaths per year caused by Plasmodium falciparum. Most antimalarial drugs face decreased efficacy due to the emergence of resistant parasites, which necessitates the discovery of new drugs. To identify new antimalarials, we developed an automated 384-well plate screening assay using P. falciparum parasites that stably express cytoplasmic firefly luciferase. After initial optimization, we tested two different types of compound libraries: known bioactive collections (Library of Pharmacologically Active Compounds [LOPAC] and the library from the National Institute of Neurological Disorders and Stroke [NINDS]) and a library of uncharacterized compounds (ChemBridge). A total of 12,320 compounds were screened at 5.5 μM. Selecting only compounds that reduced parasite growth by 85% resulted in 33 hits from the combined bioactive collection and 130 hits from the ChemBridge library. Fifteen novel drug-like compounds from the bioactive collection were found to be active against P. falciparum. Twelve new chemical scaffolds were found from the ChemBridge hits, the most potent of which was a series based on the 1,4-naphthoquinone scaffold, which is structurally similar to the FDA-approved antimalarial atovaquone. However, in contrast to atovaquone, which acts to inhibit the bc 1 complex and block the electron transport chain in parasite mitochondria, we have determined that our new 1,4-napthoquinones act in a novel, non-bc 1-dependent mechanism and remain potent against atovaquone- and chloroquine-resistant parasites. Ultimately, this study may provide new probes to understand the molecular details of the malaria life cycle and to identify new antimalarials.
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N., Raghu Murthy, and Seema Rai. "Analysis of clinical profile and prescription pattern of malaria in a tertiary care hospital in Karnataka, India." International Journal of Basic & Clinical Pharmacology 8, no. 8 (July 23, 2019): 1744. http://dx.doi.org/10.18203/2319-2003.ijbcp20193136.
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Background: Malaria is one of the leading causes of morbidity and mortality in developing countries like India. Plasmodium falciparum and Plasmodium vivax are the commonest species implicated for an increased incidence of malaria in India. The pattern of disease, signs, and symptoms vary from place to place, region to region due to demographic variations. The current study was undertaken to study the differences in the clinical profile of malaria, particularly signs and symptoms, complications and response to treatment in malaria.Methods: A retrospective, single center, surveillance study was carried out at a tertiary health care center in Mangalore. All patients aged above 18 years diagnosed as malaria by peripheral smear method and rapid diagnostic tests were included in the study. The clinical features, complications, and response to treatment were noted.Results: Fifty eight patients diagnosed as malaria were included in the study. Compared to other studies and nationwide incidences, here P. vivax emerged as the leading cause of malaria. All patients presented with fever varying from 3-20 days. About 30 patients complained of headache and 21 patients presented with malaise. In about 6 patient’s complications were seen. Majority of patients received artemisinin derivatives followed by chloroquine for treatment of malariaConclusions: Previous thinking that complications are only seen with P. falciparum has to be changed. Now many complications, mild as well as severe type are seen in P. vivax malaria. Drug resistance is another global problem which needs to be tackled wisely by systematic usage of antimalarials.