scholarly journals Ex VivoActivity of Endoperoxide Antimalarials, Including Artemisone and Arterolane, against Multidrug-Resistant Plasmodium falciparum Isolates from Cambodia

2014 ◽  
Vol 58 (10) ◽  
pp. 5831-5840 ◽  
Author(s):  
Charlotte A. Lanteri ◽  
Suwanna Chaorattanakawee ◽  
Chanthap Lon ◽  
David L. Saunders ◽  
Wiriya Rutvisuttinunt ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Ex Vivo ◽  
Geometric Mean ◽  
Artemisinin Resistance ◽  
Multidrug Resistant ◽  
Chloroquine Resistance ◽  
Enzyme Linked Immunosorbent Assay ◽  
Multidrug Resistance Gene ◽  
Content Type ◽  
Clinical Resistance

ABSTRACTNovel synthetic endoperoxides are being evaluated as new components of artemisinin combination therapies (ACTs) to treat artemisinin-resistantPlasmodium falciparummalaria. We conducted blindedex vivoactivity testing of fully synthetic (OZ78 and OZ277) and semisynthetic (artemisone, artemiside, artesunate, and dihydroartemisinin) endoperoxides in the histidine-rich protein 2 enzyme-linked immunosorbent assay against 200P. falciparumisolates from areas of artemisinin-resistant malaria in western and northern Cambodia in 2009 and 2010. The order of potency and geometric mean (GM) 50% inhibitory concentrations (IC50s) were as follows: artemisone (2.40 nM) > artesunate (8.49 nM) > dihydroartemisinin (11.26 nM) > artemiside (15.28 nM) > OZ277 (31.25 nM) > OZ78 (755.27 nM).Ex vivoactivities of test endoperoxides positively correlated with dihydroartemisinin and artesunate. The isolates were over 2-fold less susceptible to dihydroartemisinin than the artemisinin-sensitiveP. falciparumW2 clone and showed sensitivity comparable to those with test endoperoxides and artesunate, with isolate/W2 IC50susceptibility ratios of <2.0. All isolates hadP. falciparumchloroquine resistance transporter mutations, with negative correlations in sensitivity to endoperoxides and chloroquine. The activities of endoperoxides (artesunate, dihydroartemisinin, OZ277, and artemisone) significantly correlated with that of the ACT partner drug, mefloquine. Isolates had mutations associated with clinical resistance to mefloquine, with 35% prevalence ofP. falciparummultidrug resistance gene 1 (pfmdr1) amplification and 84.5% occurrence of thepfmdr1Y184F mutation. GM IC50s for mefloquine, lumefantrine, and endoperoxides (artesunate, dihydroartemisinin, OZ277, OZ78, and artemisone) correlated withpfmdr1copy number. Given that current ACTs are failing potentially from reduced sensitivity to artemisinins and partner drugs, newly identified mutations associated with artemisinin resistance reported in the literature andpfmdr1mutations should be examined for their combined contributions to emerging ACT resistance.

scholarly journals Ex VivoDrug Susceptibility Testing and Molecular Profiling of Clinical Plasmodium falciparum Isolates from Cambodia from 2008 to 2013 Suggest Emerging Piperaquine Resistance

2015 ◽  
Vol 59 (8) ◽  
pp. 4631-4643 ◽  
Author(s):  
Suwanna Chaorattanakawee ◽  
David L. Saunders ◽  
Darapiseth Sea ◽  
Nitima Chanarat ◽  
Kritsanai Yingyuen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Ex Vivo ◽  
Artemisinin Combination Therapy ◽  
Artemisinin Resistance ◽  
Drug Susceptibility ◽  
Chloroquine Resistance ◽  
First Line ◽  
Content Type

ABSTRACTCambodia's first-line artemisinin combination therapy, dihydroartemisinin-piperaquine (DHA-PPQ), is no longer sufficiently curative against multidrug-resistantPlasmodium falciparummalaria at some Thai-Cambodian border regions. We report recent (2008 to 2013) drug resistance trends in 753 isolates from northern, western, and southern Cambodia by surveying forex vivodrug susceptibility and molecular drug resistance markers to guide the selection of an effective alternative to DHA-PPQ. Over the last 3 study years, PPQ susceptibility declined dramatically (geomean 50% inhibitory concentration [IC50] increased from 12.8 to 29.6 nM), while mefloquine (MQ) sensitivity doubled (67.1 to 26 nM) in northern Cambodia. These changes in drug susceptibility were significantly associated with a decreased prevalence ofP. falciparummultidrug resistance 1 gene (Pfmdr1) multiple copy isolates and coincided with the timing of replacing artesunate-mefloquine (AS-MQ) with DHA-PPQ as the first-line therapy. Widespread chloroquine resistance was suggested by all isolates being of theP. falciparumchloroquine resistance transporter gene CVIET haplotype. Nearly all isolates collected from the most recent years hadP. falciparumkelch13mutations, indicative of artemisinin resistance.Ex vivobioassay measurements of antimalarial activity in plasma indicated 20% of patients recently took antimalarials, and their plasma had activity (median of 49.8 nM DHA equivalents) suggestive of substantialin vivodrug pressure. Overall, our findings suggest DHA-PPQ failures are associated with emerging PPQ resistance in a background of artemisinin resistance. The observed connection between drug policy changes and significant reduction in PPQ susceptibility with mitigation of MQ resistance supports reintroduction of AS-MQ, in conjunction with monitoring of theP. falciparummdr1copy number, as a stop-gap measure in areas of DHA-PPQ failure.

scholarly journals Ex VivoSusceptibility of Plasmodium falciparum to Antimalarial Drugs in Western, Northern, and Eastern Cambodia, 2011-2012: Association with Molecular Markers

2013 ◽  
Vol 57 (11) ◽  
pp. 5277-5283 ◽  
Author(s):  
Pharath Lim ◽  
Dalin Dek ◽  
Vorleak Try ◽  
Richard T. Eastman ◽  
Sophy Chy ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Copy Number ◽  
Ex Vivo ◽  
Geometric Mean ◽  
Multidrug Resistant ◽  
Parasite Resistance ◽  
Resistance Marker ◽  
First Line ◽  
Content Type ◽  
Preah Vihear

ABSTRACTIn 2008, dihydroartemisinin (DHA)-piperaquine (PPQ) became the first-line treatment for uncomplicatedPlasmodium falciparummalaria in western Cambodia. Recent reports of increased treatment failure rates after DHA-PPQ therapy in this region suggest that parasite resistance to DHA, PPQ, or both is now adversely affecting treatment. While artemisinin (ART) resistance is established in western Cambodia, there is no evidence of PPQ resistance. To monitor for resistance to PPQ and other antimalarials, we measured drug susceptibilities for parasites collected in 2011 and 2012 from Pursat, Preah Vihear, and Ratanakiri, in western, northern, and eastern Cambodia, respectively. Using a SYBR green I fluorescence assay, we calculated theex vivo50% inhibitory concentrations (IC50s) of 310 parasites to six antimalarials: chloroquine (CQ), mefloquine (MQ), quinine (QN), PPQ, artesunate (ATS), and DHA. Geometric mean IC50s (GMIC50s) for all drugs (except PPQ) were significantly higher in Pursat and Preah Vihear than in Ratanakiri (P≤ 0.001). An increased copy number ofP. falciparummdr1(pfmdr1), an MQ resistance marker, was more prevalent in Pursat and Preah Vihear than in Ratanakiri and was associated with higher GMIC50s for MQ, QN, ATS, and DHA. An increased copy number of a chromosome 5 region (X5r), a candidate PPQ resistance marker, was detected in Pursat but was not associated with reduced susceptibility to PPQ. Theex vivoIC50andpfmdr1copy number are important tools in the surveillance of multidrug-resistant (MDR) parasites in Cambodia. While MDRP. falciparumis prevalent in western and northern Cambodia, there is no evidence for PPQ resistance, suggesting that DHA-PPQ treatment failures result mainly from ART resistance.

scholarly journals Ex VivoDrug Susceptibility of Ferroquine against Chloroquine-Resistant Isolates of Plasmodium falciparum and P. vivax

2011 ◽  
Vol 55 (9) ◽  
pp. 4461-4464 ◽  
Author(s):  
Jutta Marfurt ◽  
Ferryanto Chalfein ◽  
Pak Prayoga ◽  
Frans Wabiser ◽  
Enny Kenangalem ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Combination Therapy ◽  
Drug Class ◽  
Ex Vivo ◽  
Multidrug Resistant ◽  
Drug Action ◽  
Drug Uptake ◽  
Content Type ◽  
Excellent Activity

ABSTRACTFerroquine (FQ; SSR97193), a ferrocene-containing 4-aminoquinoline derivate, has potentin vitroefficacy against chloroquine (CQ)-resistantPlasmodium falciparumand CQ-sensitiveP. vivax. In the current study,ex vivoFQ activity was tested in multidrug-resistantP. falciparumandP. vivaxfield isolates using a schizont maturation assay. Although FQ showed excellent activity against CQ-sensitive and -resistantP. falciparumandP. vivax(median 50% inhibitory concentrations [IC50s], 9.6 nM and 18.8 nM, respectively), there was significant cross-susceptibility with the quinoline-based drugs chloroquine, amodiaquine, and piperaquine (forP. falciparum,r= 0.546 to 0.700,P< 0.001; forP. vivax,r= 0.677 to 0.821,P< 0.001). The observedex vivocross-susceptibility is likely to reflect similar mechanisms of drug uptake/efflux and modes of drug action of this drug class. However, the potent activity of FQ against resistant isolates of bothP. falciparumandP. vivaxhighlights a promising role for FQ as a lead antimalarial against CQ-resistantPlasmodiumand a useful partner drug for artemisinin-based combination therapy.

scholarly journals ContrastingEx VivoEfficacies of “Reversed Chloroquine” Compounds in Chloroquine-Resistant Plasmodium falciparum and P. vivax Isolates

2015 ◽  
Vol 59 (9) ◽  
pp. 5721-5726 ◽  
Author(s):  
Grennady Wirjanata ◽  
Boni F. Sebayang ◽  
Ferryanto Chalfein ◽  
Prayoga ◽  
Irene Handayuni ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Ex Vivo ◽  
Rank Correlation ◽  
Multidrug Resistant ◽  
Content Type ◽  
Reversal Agents ◽  
Field Isolates ◽  
Spearman’S Rank Correlation ◽  
Spearman’S Rank Correlation Coefficient ◽  
Potential Use

ABSTRACTChloroquine (CQ) has been the mainstay of malaria treatment for more than 60 years. However, the emergence and spread of CQ resistance now restrict its use to only a few areas where malaria is endemic. The aim of the present study was to investigate whether a novel combination of a CQ-like moiety and an imipramine-like pharmacophore can reverse CQ resistanceex vivo. Between March to October 2011 and January to September 2013, two “reversed chloroquine” (RCQ) compounds (PL69 and PL106) were tested against multidrug-resistant field isolates ofPlasmodium falciparum(n= 41) andPlasmodium vivax(n= 45) in Papua, Indonesia, using a modifiedex vivoschizont maturation assay. The RCQ compounds showed high efficacy against both CQ-resistantP. falciparumandP. vivaxfield isolates. ForP. falciparum, the median 50% inhibitory concentrations (IC50s) were 23.2 nM for PL69 and 26.6 nM for PL106, compared to 79.4 nM for unmodified CQ (P< 0.001 andP= 0.036, respectively). The corresponding values forP. vivaxwere 19.0, 60.0, and 60.9 nM (P< 0.001 andP= 0.018, respectively). There was a significant correlation between IC50s of CQ and PL69 (Spearman's rank correlation coefficient [rs] = 0.727,P< 0.001) and PL106 (rs= 0.830,P< 0.001) inP. vivaxbut not inP. falciparum. Both RCQs were equally active against the ring and trophozoite stages ofP. falciparum, but inP. vivax, PL69 and PL106 showed less potent activity against trophozoite stages (median IC50s, 130.2 and 172.5 nM) compared to ring stages (median IC50s, 17.6 and 91.3 nM). RCQ compounds have enhancedex vivoactivity against CQ-resistant clinical isolates ofP. falciparumandP. vivax, suggesting the potential use of reversal agents in antimalarial drug development. Interspecies differences in RCQ compound activity may indicate differences in CQ pharmacokinetics between the twoPlasmodiumspecies.

scholarly journals Significant Efficacy of a Single Low Dose of Primaquine Compared to Stand-Alone Artemisinin Combination Therapy in Reducing Gametocyte Carriage in Cambodian Patients with Uncomplicated Multidrug-Resistant Plasmodium falciparum Malaria

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Amélie Vantaux ◽  
Saorin Kim ◽  
Eakpor Piv ◽  
Sophy Chy ◽  
Laura Berne ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Low Dose ◽  
Negative Impact ◽  
Controlled Trial ◽  
Artemisinin Combination Therapy ◽  
Artemisinin Resistance ◽  
Multidrug Resistant ◽  
Transmission Blocking ◽  
Content Type ◽  
Gametocyte Carriage

ABSTRACT Since 2012, a single low dose of primaquine (SLDPQ; 0.25 mg/kg of body weight) with artemisinin-based combination therapies has been recommended as the first-line treatment of acute uncomplicated Plasmodium falciparum malaria to interrupt its transmission, especially in low-transmission settings of multidrug resistance, including artemisinin resistance. Policy makers in Cambodia have been reluctant to implement this recommendation due to primaquine safety concerns and a lack of data on its efficacy. In this randomized controlled trial, 109 Cambodians with acute uncomplicated P. falciparum malaria received dihydroartemisinin-piperaquine (DP) alone or combined with SLDPQ on the first treatment day. The transmission-blocking efficacy of SLDPQ was evaluated on days 0, 1, 2, 3, 7, 14, 21, and 28, and recrudescence by reverse transcriptase PCR (RT-PCR) (gametocyte prevalence) and membrane feeding assays with Anopheles minimus mosquitoes (gametocyte infectivity). Without the influence of recrudescent infections, DP-SLDPQ reduced gametocyte carriage 3-fold compared to that achieved with DP. Of 48 patients tested on day 0, only 3 patients were infectious to mosquitoes (∼6%). Posttreatment, three patients were infectious on day 14 (3.5%, 1/29) and on the 1st and 7th days of recrudescence (8.3%, 1/12 for each); this overall low infectivity precluded our ability to assess its transmission-blocking efficacy. Our study confirms the effective gametocyte clearance of SLDPQ when combined with DP in multidrug-resistant P. falciparum infections and the negative impact of recrudescent infections due to poor DP efficacy. Artesunate-mefloquine (ASMQ) has replaced DP, and ASMQ-SLDPQ has been deployed to treat all patients with symptomatic P. falciparum infections to further support the elimination of multidrug-resistant P. falciparum in Cambodia. (This study has been registered at ClinicalTrials.gov under identifier NCT02434952.)

scholarly journals Plasmodium falciparum Polymorphisms Associated withEx VivoDrug Susceptibility and Clinical Effectiveness of Artemisinin-Based Combination Therapies in Benin

2013 ◽  
Vol 58 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Sabina Dahlström ◽  
Agnès Aubouy ◽  
Oumou Maïga-Ascofaré ◽  
Jean-François Faucher ◽  
Abel Wakpo ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Ex Vivo ◽  
Clinical Effectiveness ◽  
Drug Susceptibility ◽  
Fixed Dose ◽  
Enzyme Linked Immunosorbent Assay ◽  
Recurrent Infections ◽  
Combination Therapies ◽  
Content Type ◽  
Selection Of

ABSTRACTArtemisinin-based combination therapies (ACTs) are the main option to treat malaria, and their efficacy and susceptibility must be closely monitored to avoid resistance. We assessed the association ofPlasmodium falciparumpolymorphisms andex vivodrug susceptibility with clinical effectiveness. Patients enrolled in an effectiveness trial comparing artemether-lumefantrine (n= 96), fixed-dose artesunate-amodiaquine (n= 96), and sulfadoxine-pyrimethamine (n= 48) for the treatment of uncomplicated malaria 2007 in Benin were assessed.pfcrt,pfmdr1,pfmrp1,pfdhfr, andpfdhpspolymorphisms were analyzed pretreatment and in recurrent infections. Drug susceptibility was determined in fresh baseline isolates byPlasmodiumlactate dehydrogenase enzyme-linked immunosorbent assay (ELISA). A majority had 50% inhibitory concentration (IC50) estimates (the concentration required for 50% growth inhibition) lower than those of the 3D7 reference clone for desethylamodiaquine, lumefantrine, mefloquine, and quinine and was considered to be susceptible, while dihydroartemisinin and pyrimethamine IC50s were higher. No association was found between susceptibility to the ACT compounds and treatment outcome. Selection was observed for thepfmdr1N86 allele in artemether-lumefantrine recrudescences (recurring infections) (4/7 [57.1%] versus 36/195 [18.5%]), and of the opposite allele, 86Y, in artesunate-amodiaquine reinfections (new infections) (20/22 [90.9%] versus 137/195 [70.3%]) compared to baseline infections. The importance ofpfmdr1N86 in lumefantrine tolerance was emphasized by its association with elevated lumefantrine IC50s. Genetic linkage between N86 and Y184 was observed, which together with the low frequency of 1246Y may explain regional differences in selection ofpfmdr1loci. Selection of opposite alleles in artemether-lumefantrine and artesunate-amodiaquine recurrent infections supports the strategy of multiple first-line treatment. Surveillance based on clinical,ex vivo, molecular, and pharmacological data is warranted.

scholarly journals ComparativeEx VivoActivity of Novel Endoperoxides in Multidrug-Resistant Plasmodium falciparum and P. vivax

2012 ◽  
Vol 56 (10) ◽  
pp. 5258-5263 ◽  
Author(s):  
Jutta Marfurt ◽  
Ferryanto Chalfein ◽  
Pak Prayoga ◽  
Frans Wabiser ◽  
Grennady Wirjanata ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Ex Vivo ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Intrinsic Activity ◽  
Drug Resistant ◽  
The Novel ◽  
Content Type ◽  
Artemisinin Derivatives

ABSTRACTThe declining efficacy of artemisinin derivatives againstPlasmodium falciparumhighlights the urgent need to identify alternative highly potent compounds for the treatment of malaria. In Papua Indonesia, where multidrug resistance has been documented against bothP. falciparumandP. vivaxmalaria, comparativeex vivoantimalarial activity againstPlasmodiumisolates was assessed for the artemisinin derivatives artesunate (AS) and dihydroartemisinin (DHA), the synthetic peroxides OZ277 and OZ439, the semisynthetic 10-alkylaminoartemisinin derivatives artemisone and artemiside, and the conventional antimalarial drugs chloroquine (CQ), amodiaquine (AQ), and piperaquine (PIP).Ex vivodrug susceptibility was assessed in 46 field isolates (25P. falciparumand 21P. vivax). The novel endoperoxide compounds exhibited potentex vivoactivity against both species, but significant differences in intrinsic activity were observed. Compared to AS and its active metabolite DHA, all the novel compounds showed lower or equal 50% inhibitory concentrations (IC50s) in both species (median IC50s between 1.9 and 3.6 nM inP. falciparumand 0.7 and 4.6 nM inP. vivax). The antiplasmodial activity of novel endoperoxides showed different cross-susceptibility patterns in the twoPlasmodiumspecies: whereas theirex vivoactivity correlated positively with CQ, PIP, AS, and DHA inP. falciparum, the same was not apparent inP. vivax. The current study demonstrates for the first time potent activity of novel endoperoxides against drug-resistantP. vivax. The high activity against drug-resistant strains of bothPlasmodiumspecies confirms these compounds to be promising candidates for future artemisinin-based combination therapy (ACT) regimens in regions of coendemicity.

scholarly journals Identification and Deconvolution of Cross-Resistance Signals from Antimalarial Compounds Using Multidrug-Resistant Plasmodium falciparum Strains

2014 ◽  
Vol 59 (2) ◽  
pp. 1110-1118 ◽  
Author(s):  
Monika Chugh ◽  
Christian Scheurer ◽  
Sibylle Sax ◽  
Elizabeth Bilsland ◽  
Donelly A. van Schalkwyk ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Mode Of Action ◽  
De Novo ◽  
Real Life ◽  
Multidrug Resistant ◽  
Chloroquine Resistance ◽  
Cross Resistance ◽  
Content Type ◽  
Antimalarial Compounds

ABSTRACTPlasmodium falciparum, the most deadly agent of malaria, displays a wide variety of resistance mechanisms in the field. The ability of antimalarial compounds in development to overcome these must therefore be carefully evaluated to ensure uncompromised activity against real-life parasites. We report here on the selection and phenotypic as well as genotypic characterization of a panel of sensitive and multidrug-resistantP. falciparumstrains that can be used to optimally identify and deconvolute the cross-resistance signals from an extended panel of investigational antimalarials. As a case study, the effectiveness of the selected panel of strains was demonstrated using the 1,2,4-oxadiazole series, a newly identified antimalarial series of compounds within vitroactivity againstP. falciparumat nanomolar concentrations. This series of compounds was to be found inactive against several multidrug-resistant strains, and the deconvolution of this signal implicatedpfcrt, the genetic determinant of chloroquine resistance. Targeted mode-of-action studies further suggested that this new chemical series might act as falcipain 2 inhibitors, substantiating the suggestion that these compounds have a site of action similar to that of chloroquine but a distinct mode of action. New antimalarials must overcome existing resistance and, ideally, prevent itsde novoappearance. The panel of strains reported here, which includes recently collected as well as standard laboratory-adapted field isolates, is able to efficiently detect and precisely characterize cross-resistance and, as such, can contribute to the faster development of new, effective antimalarial drugs.

scholarly journals Artemisinin-Resistant Plasmodium falciparum Parasites Exhibit Altered Patterns of Development in Infected Erythrocytes

2015 ◽  
Vol 59 (6) ◽  
pp. 3156-3167 ◽  
Author(s):  
Amanda Hott ◽  
Debora Casandra ◽  
Kansas N. Sparks ◽  
Lindsay C. Morton ◽  
Geocel-Grace Castanares ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Artemisinin Resistance ◽  
Drug Pressure ◽  
Content Type ◽  
Phenotypic Resistance ◽  
Artemisinin Derivatives ◽  
Stage Of Development ◽  
Clinical Resistance

ABSTRACTArtemisinin derivatives are used in combination with other antimalarial drugs for treatment of multidrug-resistant malaria worldwide. Clinical resistance to artemisinin recently emerged in southeast Asia, yetin vitrophenotypes for discerning mechanism(s) of resistance remain elusive. Here, we describe novel phenotypic resistance traits expressed by artemisinin-resistantPlasmodium falciparum. The resistant parasites exhibit altered patterns of development that result in reduced exposure to drug at the most susceptible stage of development in erythrocytes (trophozoites) and increased exposure in the most resistant stage (rings). In addition, a novelin vitrodelayed clearance assay (DCA) that assesses drug effects on asexual stages was found to correlate with parasite clearance half-lifein vivoas well as with mutations in the Kelch domain gene associated with resistance (Pf3D7_1343700). Importantly, all of the resistance phenotypes were stable in cloned parasites for more than 2 years without drug pressure. The results demonstrate artemisinin-resistantP. falciparumhas evolved a novel mechanism of phenotypic resistance to artemisinin drugs linked to abnormal cell cycle regulation. These results offer insights into a novel mechanism of drug resistance inP. falciparumand new tools for monitoring the spread of artemisinin resistance.

scholarly journals The Spiroindolone KAE609 Does Not Induce Dormant Ring Stages in Plasmodium falciparum Parasites

2016 ◽  
Vol 60 (9) ◽  
pp. 5167-5174 ◽  
Author(s):  
Marina Chavchich ◽  
Karin Van Breda ◽  
Kerryn Rowcliffe ◽  
Thierry T. Diagana ◽  
Michael D. Edstein
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Arrest ◽  
Artemisinin Resistance ◽  
Multidrug Resistant ◽  
The Novel ◽  
Ring Stage ◽  
Content Type ◽  
Artemisinin Derivatives ◽  
Temporary Growth

ABSTRACTIn vitrodrug treatment with artemisinin derivatives, such as dihydroartemisinin (DHA), results in a temporary growth arrest (i.e., dormancy) at an early ring stage inPlasmodium falciparum. This response has been proposed to play a role in the recrudescence ofP. falciparuminfections following monotherapy with artesunate and may contribute to the development of artemisinin resistance inP. falciparummalaria. We demonstrate here that artemether does induce dormant rings, a finding which further supports the class effect of artemisinin derivatives in inducing the temporary growth arrest ofP. falciparumparasites. In contrast and similarly to lumefantrine, the novel and fast-acting spiroindolone compound KAE609 does not induce growth arrest at the early ring stage ofP. falciparumand prevents the recrudescence of DHA-arrested rings at a low concentration (50 nM). Our findings, together with previous clinical data showing that KAE609 is active against artemisinin-resistant K13 mutant parasites, suggest that KAE609 could be an effective partner drug with a broad range of antimalarials, including artemisinin derivatives, in the treatment of multidrug-resistantP. falciparummalaria.

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