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https://www.readbyqxmd.com/read/29348637/plasmodium-dihydrofolate-reductase-is-a-second-enzyme-target-for-the-antimalarial-action-of-triclosan
#1
Elizabeth Bilsland, Liisa van Vliet, Kevin Williams, Jack Feltham, Marta P Carrasco, Wesley L Fotoran, Eliana F G Cubillos, Gerhard Wunderlich, Morten Grøtli, Florian Hollfelder, Victoria Jackson, Ross D King, Stephen G Oliver
Malaria, caused by parasites of the genus Plasmodium, leads to over half a million deaths per year, 90% of which are caused by Plasmodium falciparum. P. vivax usually causes milder forms of malaria; however, P. vivax can remain dormant in the livers of infected patients for weeks or years before re-emerging in a new bout of the disease. The only drugs available that target all stages of the parasite can lead to severe side effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency; hence, there is an urgent need to develop new drugs active against blood and liver stages of the parasite...
January 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29342187/induction-of-high-tolerance-to-artemisinin-by-sub-lethal-administration-a-new-in-vitro-model-of-p-falciparum
#2
Serena De Lucia, Ioannis Tsamesidis, Maria Carmina Pau, Kristina R Kesely, Antonella Pantaleo, Francesco Turrini
Artemisinin resistance is a major threat to malaria control efforts. Resistance is characterized by an increase in the Plasmodium falciparum parasite clearance half-life following treatment with artemisinin-based combination therapies (ACTs) and an increase in the percentage of surviving parasites. The remarkably short blood half-life of artemisinin derivatives may contribute to drug-resistance, possibly through factors including sub-lethal plasma concentrations and inadequate exposure. Here we selected for a new strain of artemisinin resistant parasites, termed the artemisinin resistant strain 1 (ARS1), by treating P...
2018: PloS One
https://www.readbyqxmd.com/read/29336544/identification-of-collateral-sensitivity-to-dihydroorotate-dehydrogenase-inhibitors-in-i-plasmodium-falciparum-i
#3
Leila Saxby Ross, Maria Jose Lafuente-Monasterio, Tomoyo Sakata-Kato, Rebecca E K Mandt, Francisco-Javier Gamo, Dyann F Wirth, Amanda K Lukens
Drug resistance has been reported for every antimalarial in use highlighting the need for new strategies to protect the efficacy of therapeutics in development. We have previously shown that resistance can be suppressed with a population biology trap: by identifying situations where resistance to one compound confers hypersensitivity to another (collateral sensitivity), we can design combination therapies that not only kill the parasite, but also guide its evolution away from resistance. We applied this concept to the Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme, a well validated antimalarial target with inhibitors in the development pipeline...
January 16, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29333044/antiplasmodial-activity-of-isolated-polyphenols-from-alectryon-serratus-leaves-against-3d7-plasmodium-falciparum
#4
Uswatun Khasanah, Aty WidyaWaruyanti, Achmad Fuad Hafid, Mulyadi Tanjung
Background: Alectryon serratus was selected from a screening program devoted to search naturally occurring antimalarial compound from plants in Alas Purwo National Park, Banyuwangi, East Java, Indonesia. The previous studies showed that ethanol extract of A. serratus leaves contains some polyphenol compounds. Objective: This study was designed to isolate and investigate antiplasmodial activity of polyphenol compounds. Material and Methods: The ethanol extract of A...
December 2017: Pharmacognosy Research
https://www.readbyqxmd.com/read/29327915/multispectral-atomic-force-microscopy-infrared-nano-imaging-of-malaria-infected-red-blood-cells
#5
David Perez-Guaita, Kamila Kochan, Mitchell Batty, Christian Doerig, Jose Garcia-Bustos, Shirley Josefina Espinoza Herrera, Don McNaughton, Philip Heraud, Bayden R Wood
Atomic Force Microscopy-Infrared (AFM-IR) spectroscopy is a powerful new technique that can be applied to study molecular composition of cells and tissues at the nano-scale. AFM-IR maps are acquired using single wavenumber value: they show either the absorbance plotted against a single wavenumber value, or a ratio of two absorbance values. Here we implement multivariate image analysis to generate multivariate AFM-IR maps, and use this approach to resolve subcellular structural information in red blood cells infected with Plasmodium falciparum at different stages of development...
January 12, 2018: Analytical Chemistry
https://www.readbyqxmd.com/read/29326268/mapping-the-malaria-parasite-druggable-genome-by-using-in-vitro-evolution-and-chemogenomics
#6
Annie N Cowell, Eva S Istvan, Amanda K Lukens, Maria G Gomez-Lorenzo, Manu Vanaerschot, Tomoyo Sakata-Kato, Erika L Flannery, Pamela Magistrado, Edward Owen, Matthew Abraham, Gregory LaMonte, Heather J Painter, Roy M Williams, Virginia Franco, Maria Linares, Ignacio Arriaga, Selina Bopp, Victoria C Corey, Nina F Gnädig, Olivia Coburn-Flynn, Christin Reimer, Purva Gupta, James M Murithi, Pedro A Moura, Olivia Fuchs, Erika Sasaki, Sang W Kim, Christine H Teng, Lawrence T Wang, Aslı Akidil, Sophie Adjalley, Paul A Willis, Dionicio Siegel, Olga Tanaseichuk, Yang Zhong, Yingyao Zhou, Manuel Llinás, Sabine Ottilie, Francisco-Javier Gamo, Marcus C S Lee, Daniel E Goldberg, David A Fidock, Dyann F Wirth, Elizabeth A Winzeler
Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target-inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea...
January 12, 2018: Science
https://www.readbyqxmd.com/read/29325595/mortality-impact-of-an-increased-blood-glucose-cut-off-level-for-hypoglycaemia-treatment-in-severely-sick-children-in-malawi-sugarfact-trial-study-protocol-for-a-randomised-controlled-trial
#7
Tim Baker, Queen Dube, Josephine Langton, Helena Hildenwall
BACKGROUND: Mortality in children remains high in sub-Saharan African hospitals. While antimalarial drugs, antibiotics and other definitive treatments are well understood, the role of emergency care with supportive therapies, such as maintaining normal glucose and electrolyte balances, has been given limited attention. Hypoglycaemia is common in children admitted to hospital in low-income settings. The current definition of hypoglycaemia is a blood glucose level < 2.5 mmol/L in a well-nourished child...
January 11, 2018: Trials
https://www.readbyqxmd.com/read/29324340/antimalarial-naphthoquinones-synthesis-via-click-chemistry-in%C3%A2-vitro-activity-docking-to-pfdhodh-and-sar-of-lapachol-based-compounds
#8
Geraldo Célio Brandão, Franciele C Rocha Missias, Lucas Miquéias Arantes, Luciana Ferreira Soares, Kuldeep K Roy, Robert J Doerksen, Alaide Braga de Oliveira, Guilherme Rocha Pereira
Lapachol is an abundant prenyl naphthoquinone occurring in Brazilian Bignoniaceae that was clinically used, in former times, as an antimalarial drug, despite its moderate effect. Aiming to search for potentially better antimalarials, a series of 1,2,3-triazole derivatives was synthesized by chemical modification of lapachol. Alkylation of the hydroxyl group gave its propargyl ether which, via copper-catalyzed cycloaddition (CuAAC) click chemistry with different organic azides, afforded 17 naphthoquinonolyl triazole derivatives...
December 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29324251/potential-role-of-plasmodium-falciparum-exported-protein-1-in-the-chloroquine-mode-of-action
#9
Andreas Martin Lisewski, Joel Patrick Quiros, Monica Mittal, Nagireddy Putluri, Arun Sreekumar, Jesper Z Haeggström, Olivier Lichtarge
In the human malaria parasite Plasmodium falciparum, membrane glutathione S-transferases (GST) have recently emerged as potential cellular detoxifying units and as drug target candidates with the artemisinin (ART) class of antimalarials inhibiting their activity at single-digit nanomolar potency when activated by iron sources such as cytotoxic hematin. Here we put forward the hypothesis that the membrane GST Plasmodium falciparum exported protein 1 (PfEXP1, PF3D7_1121600) might be directly involved in the mode of action of the unrelated antimalarial 4-aminoquinoline drug chloroquine (CQ)...
December 27, 2017: International Journal for Parasitology, Drugs and Drug Resistance
https://www.readbyqxmd.com/read/29321371/assessing-drug-efficacy-against-plasmodium-falciparum-liver-stages-in-vivo
#10
Erika L Flannery, Lander Foquet, Vorada Chuenchob, Matthew Fishbaugher, Zachary Billman, Mary Jane Navarro, William Betz, Tayla M Olsen, Joshua Lee, Nelly Camargo, Thao Nguyen, Carola Schafer, Brandon K Sack, Elizabeth M Wilson, Jessica Saunders, John Bial, Brice Campo, Susan A Charman, Sean C Murphy, Margaret A Phillips, Stefan Hi Kappe, Sebastian A Mikolajczak
Malaria eradication necessitates new tools to fight the evolving and complex Plasmodium pathogens. These tools include prophylactic drugs that eliminate Plasmodium liver stages and consequently prevent clinical disease, decrease transmission, and reduce the propensity for resistance development. Currently, the identification of these drugs relies on in vitro P. falciparum liver stage assays or in vivo causal prophylaxis assays using rodent malaria parasites; there is no method to directly test in vivo liver stage activity of candidate antimalarials against the human malaria-causing parasite P...
January 11, 2018: JCI Insight
https://www.readbyqxmd.com/read/29320822/antimalarial-activity-of-c-10-substituted-triazolyl-artemisinin
#11
Gab-Man Park, Hyun Park, Sangtae Oh, Seokjoon Lee
We synthesized C-10 substituted triazolyl artemisinins by the Huisgen cycloaddition reaction between dihydroartemisinins (2) and variously substituted 1, 2, 3-triazoles (8a-8h). The antimalarial activities of 32 novel artemisinin derivatives were screened against a chloroquine-resistant parasite. Among them, triazolyl artemisinins with electron-withdrawing groups showed stronger antimalarial activities than those shown by the derivatives having electron-donating groups. In particularly, m-chlorotriazolyl artemisinin (9d-12d) showed antimalarial activity equivalent to that of artemisinin and could be a strong drug candidate...
December 2017: Korean Journal of Parasitology
https://www.readbyqxmd.com/read/29320160/efforts-aimed-to-reduce-attrition-in-antimalarial-drug-discovery-a-systematic-evaluation-of-current-antimalarial-targets-portfolio
#12
María Jesus Chaparro, Felix Calderon, Pablo Castañeda, Elena Fernandez Alvaro, Raquel Gabarro, Francisco-Javier Gamo, María G Gómez-Lorenzo, Julio Martín, Esther Fernandez
Malaria remains a major global health problem. In 2015 alone, more than 200 million cases of malaria were reported, and more than 400,000 deaths occurred. Since 2010, emerging resistance to current front-line ACTs (Artemisinin Combination Therapies) has been detected in endemic countries. Therefore, there is an urgency for new therapies based on novel modes of action, able to relieve symptoms as fast as the artemisinins and/or block malaria transmission. During the past few years, the antimalarial community has focused their efforts on phenotypic screening as a pragmatic approach to identify new hits...
January 10, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29318942/high-prevalence-of-dihydrofolate-reductase-gene-mutations-in-plasmodium-falciparum-parasites-among-pregnant-women-in-nigeria-after-reported-use-of-sulfadoxine-pyrimethamine
#13
Olusola Ojurongbe, Christian N Nguetse, Samuel A Fayemiwo, Catherine O Falade, Taiwo A Ojurongbe, Bolaji N Thomas, Christian G Meyer, Thirumalaisamy P Velavan
This study assesses the prevalence of asymptomatic Plasmodium falciparum parasitemia positivity and P. falciparum dihydrofolate reductase (pfdhfr) mutations in parasite isolates among pregnant women in Southwest Nigeria. Plasmodium falciparum parasitemia was confirmed by microscopy and nested PCR in 200 pregnant women attending antenatal care. The prevalence of pfdhfr polymorphisms was determined by direct sequencing of the gene fragments containing the C50R, N51I, C59R, S108N, and I164L mutations. Information on the use of antimalarial drugs and methods applied to prevent malaria were obtained by a questionnaire...
January 10, 2018: Pathogens and Global Health
https://www.readbyqxmd.com/read/29315671/the-antimalarial-drug-amodiaquine-possesses-anti-zika-virus-activities
#14
Yingshan Han, Thibault Mesplède, Hongtao Xu, Yudong Quan, Mark A Wainberg
Zika virus (ZIKV) outbreak has emerged as a global health threat, particularly in tropical areas, over the past few years. No antiviral therapy or vaccine is available at present. For these reasons, repurposing clinically approved drugs against ZIKV infection may provide rapid and cost-effective global health benefits. Here we explored this strategy and screened eight FDA-approved drugs for antiviral activity against ZIKV using a cell-based assay. Our results show that the antimalarial drug amodiaquine has anti-ZIKV activity with EC50 at low micromolar concentrations in cell culture...
January 9, 2018: Journal of Medical Virology
https://www.readbyqxmd.com/read/29311093/characterization-of-the-preclinical-pharmacology-of-the-new-2-aminomethylphenol-jpc-3210-for-malaria-treatment-and-prevention
#15
Geoffrey W Birrell, Gavin D Heffernan, Guy A Schiehser, John Anderson, Arba L Ager, Pablo Morales, Donna MacKenzie, Karin van Breda, Marina Chavchich, Laura R Jacobus, G Dennis Shanks, David P Jacobus, Michael D Edstein
The new 2-aminomethylphenol JPC-3210 has potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum lines, low cytotoxicity and high in vivo efficacy against murine malaria. Here we report on the pharmacokinetics of JPC-3210 in mice and monkeys and in vitro screening assays including the inhibition of cytochrome (CYP) P450 isozymes. In mice JPC-3210 is rapidly absorbed, has extensive tissue distribution with a brain tissue to plasma concentration ratio of about 5.4 and a lengthy plasma elimination half-life of about 4...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29311086/artemether-lumefantrine-for-the-treatment-of-plasmodium-malariae-plasmodium-ovale-and-mixed-plasmodium-malaria-a-prospective-clinical-trial-assessing-species-specific-efficacy-in-gabon
#16
Mirjam Groger, Luzia Veletzky, Albert Lalremruata, Chiara Cattaneo, Johannes Mischlinger, Rella Zoleko-Manego, Lilian Endamne, Anna Klicpera, Johanna Kim, The Nguyen, Lena Flohr, Jonathan Remppis, Pierre-Blaise Matsiegui, Ayôla A Adegnika, Selidji T Agnandji, Peter G Kremsner, Benjamin Mordmüller, Ghyslain Mombo-Ngoma, Michael Ramharter
ObjectivesTreatment recommendations for Plasmodium malariae and Plasmodium ovale malaria are largely based on anecdotal evidence. The aim of this study was to systematically assess the efficacy and safety of artemether-lumefantrine for the treatment of patients with uncomplicated P.malariae or P.ovale mono-infections, or mixed Plasmodium infections.Patients and methodsThis prospective study was conducted in Gabon. Patients with microscopically confirmed P.malariae, P.ovale, or mixed species malaria with at least one of these two Plasmodium species were treated with an oral, fixed dose combination of artemether-lumefantrine for three consecutive days...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29311064/high-content-screening-of-mmv-pathogen-box-for-plasmodium-falciparum-digestive-vacuole-disrupting-molecules-reveals-valuable-starting-points-for-drug-discovery
#17
Jie Xin Tong, Rajesh Chandramohanadas, Kevin Shyong-Wei Tan
Plasmodium falciparum infections leading to malaria have severe clinical manifestations and high mortality rates. Chloroquine (CQ), a former mainstay of malaria chemotherapy, has been rendered ineffective due to the emergence of wide-spread resistance. Recent studies, however, have unveiled a novel mode of action in which low micromolar levels of CQ permeabilized the parasite's digestive vacuole (DV) membrane, leading to calcium efflux, mitochondrial depolarization and DNA degradation. These phenotypes implicate the DV as an alternative target of CQ and suggests that DV disruption is an attractive target for exploitation through the screening for DV-disruptive antimalarials...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29311059/g-quadruplex-dna-motifs-in-the-malaria-parasite-plasmodium-falciparum-and-their-potential-as-novel-antimalarial-drug-targets
#18
Lynne M Harris, Katelyn R Monsell, Florian Noulin, M Toyin Famodimu, Nicolas Smargiasso, Christian Damblon, Paul Horrocks, Catherine J Merrick
G-quadruplexes are DNA or RNA secondary structures that can be formed from guanine-rich nucleic acids. These four-stranded structures, composed of stacked quartets of guanine bases, can be highly stable and have been demonstrated to occur in vivo in the DNA of human cells and other systems, where they play important biological roles, influencing processes such as telomere maintenance, DNA replication and transcription, or in the case of RNA G-quadruplexes, RNA translation and processing. We report for the first time that DNA G-quadruplexes can be detected in the nuclei of the malaria parasite Plasmodium falciparum, which has one of the most A/T-biased genomes sequenced and therefore possesses few guanine-rich sequences with the potential to form G-quadruplexes...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29309141/synthesis-and-bioactivity-of-reduced-chalcones-containing-sulfonamide-side-chains
#19
Anwar E M Noreljaleel, A Wilhelm, S L Bonnet, J H van der Westhuizen
The effect on the bioactivity of antibacterial sulfonamide drugs against malaria and tuberculosis via an increase of the lipid solubility groups by condensation with a reduced chalcone was investigated. Sulfonamide derivatives (8a-8d) were obtained via a 1,3-diarylpropane scaffold, prepared by reduction of the relevant chalcones, followed by the addition of a sulfonamide moiety via the Mannich and the Mannich exchange reactions. The ClogP values indicated that the lipophilicities of 8a-8d and intermediate reduced chalcones and N-alkylated reduced chalcones (5a-7a) were much higher than those of the sulfonamides (1a-1c)...
January 8, 2018: Journal of Natural Products
https://www.readbyqxmd.com/read/29305880/distinct-effects-of-hiv-protease-inhibitors-and-erad-inhibitors-on-zygote-to-ookinete-transition-of-the-malaria-parasite
#20
Evi Goulielmaki, Sofia Kaforou, Kannan Venugopal, Thanasis G Loukeris, Inga Siden-Kiamos, Konstantinos Koussis
In an effort to eradicate malaria, new interventions are proposed to include compound/vaccine development against pre-erythrocytic, erythrocytic and mosquito stages of Plasmodium. Drug repurposing might be an alternative approach to new antimalarials reducing the cost and the time required for drug development. Previous in vitro studies have examined the effects of protease inhibitors on different stages of the Plasmodium parasite, although the clinical relevance of this remains unclear. In this study we tested the putative effect of three HIV protease inhibitors, two general aspartyl protease inhibitors and three AAA-p97 ATPase inhibitors on the zygote to ookinete transition of the Plasmodium parasite...
January 3, 2018: Molecular and Biochemical Parasitology
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