scholarly journals Assessment of the Induction of Dormant Ring Stages in Plasmodium falciparum Parasites by Artemisone and Artemisone Entrapped in Pheroid VesiclesIn Vitro

2014 ◽  
Vol 58 (12) ◽  
pp. 7579-7582 ◽  
Author(s):  
Lizette Grobler ◽  
Marina Chavchich ◽  
Richard K. Haynes ◽  
Michael D. Edstein ◽  
Anne F. Grobler
Keyword(s):  
Plasmodium Falciparum ◽  
Delivery System ◽  
Multidrug Resistant ◽  
Content Type

ABSTRACTThein vitroantimalarial activities of artemisone and artemisone entrapped in Pheroid vesicles were compared, as was their ability to induce dormancy inPlasmodium falciparum. There was no increase in the activity of artemisone entrapped in Pheroid vesicles against multidrug-resistantP. falciparumlines. Artemisone induced the formation of dormant ring stages similar to dihydroartemisinin. Thus, the Pheroid delivery system neither improved the activity of artemisone nor prevented the induction of dormant rings.

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 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 Atovaquone-Proguanil Remains a Potential Stopgap Therapy for Multidrug-Resistant Plasmodium falciparum in Areas along the Thai-Cambodian Border

2015 ◽  
Vol 60 (3) ◽  
pp. 1896-1898 ◽  
Author(s):  
David L. Saunders ◽  
Suwanna Chaorattanakawee ◽  
Panita Gosi ◽  
Charlotte Lanteri ◽  
Sok Somethy ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Resistance Gene ◽  
Point Mutations ◽  
Multidrug Resistant ◽  
Blood Stage ◽  
Alternative Treatments ◽  
Content Type

Our recent report of dihydroartemisinin-piperaquine failure to treatPlasmodium falciparuminfections in Cambodia adds new urgency to the search for alternative treatments. Despite dihydroartemisinin-piperaquine failure, and higher piperaquine 50% inhibitory concentrations (IC50s) following reanalysis than those previously reported,P. falciparumremained sensitive to atovaquone (ATQ)in vitro. There were no point mutations in theP. falciparumcytochromebATQ resistance gene. Mefloquine, artemisinin, chloroquine, and quinine IC50s remained comparable to those from other recent reports. Atovaquone-proguanil may be a useful stopgap but remains susceptible to developing resistance when used as blood-stage therapy.

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.

scholarly journals PotentEx VivoActivity of Naphthoquine and Methylene Blue against Drug-Resistant Clinical Isolates of Plasmodium falciparum and Plasmodium vivax

2015 ◽  
Vol 59 (10) ◽  
pp. 6117-6124 ◽  
Author(s):  
Grennady Wirjanata ◽  
Boni F. Sebayang ◽  
Ferryanto Chalfein ◽  
Prayoga ◽  
Irene Handayuni ◽  
...  
Keyword(s):  
Methylene Blue ◽  
Plasmodium Falciparum ◽  
Ex Vivo ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Trophozoite Stage ◽  
Content Type ◽  
Susceptibility Data ◽  
Highly Active

ABSTRACTThe 4-aminoquinoline naphthoquine (NQ) and the thiazine dye methylene blue (MB) have potentin vitroefficacies againstPlasmodium falciparum, but susceptibility data forP. vivaxare limited. The species- and stage-specificex vivoactivities of NQ and MB were assessed using a modified schizont maturation assay on clinical field isolates from Papua, Indonesia, where multidrug-resistantP. falciparumandP. vivaxare prevalent. Both compounds were highly active againstP. falciparum(median [range] 50% inhibitory concentration [IC50]: NQ, 8.0 nM [2.6 to 71.8 nM]; and MB, 1.6 nM [0.2 to 7.0 nM]) andP. vivax(NQ, 7.8 nM [1.5 to 34.2 nM]; and MB, 1.2 nM [0.4 to 4.3 nM]). Stage-specific drug susceptibility assays revealed significantly greater IC50s in parasites exposed at the trophozoite stage than at the ring stage for NQ inP. falciparum(26.5 versus 5.1 nM,P= 0.021) andP. vivax(341.6 versus 6.5 nM,P= 0.021) and for MB inP. vivax(10.1 versus 1.6 nM,P= 0.010). The excellentex vivoactivities of NQ and MB against bothP. falciparumandP. vivaxhighlight their potential utility for the treatment of multidrug-resistant malaria in areas where both species are endemic.

scholarly journals Comparison of In Vitro Activity and MIC Distributions between the Novel Oxazolidinone Delpazolid and Linezolid against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis in China

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Zhaojing Zong ◽  
Wei Jing ◽  
Jin Shi ◽  
Shu'an Wen ◽  
Tingting Zhang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Novel Mutation ◽  
Multidrug Resistant ◽  
23S Rrna ◽  
Drug Resistant ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Significant Difference ◽  
Mdr Tb

ABSTRACT Oxazolidinones are efficacious in treating mycobacterial infections, including tuberculosis (TB) caused by drug-resistant Mycobacterium tuberculosis. In this study, we compared the in vitro activities and MIC distributions of delpazolid, a novel oxazolidinone, and linezolid against multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) in China. Additionally, genetic mutations in 23S rRNA, rplC, and rplD genes were analyzed to reveal potential mechanisms underlying the observed oxazolidinone resistance. A total of 240 M. tuberculosis isolates were included in this study, including 120 MDR-TB isolates and 120 XDR-TB isolates. Overall, linezolid and delpazolid MIC90 values for M. tuberculosis isolates were 0.25 mg/liter and 0.5 mg/liter, respectively. Based on visual inspection, we tentatively set epidemiological cutoff (ECOFF) values for MIC determinations for linezolid and delpazolid at 1.0 mg/liter and 2.0 mg/liter, respectively. Although no significant difference in resistance rates was observed between linezolid and delpazolid among XDR-TB isolates (P > 0.05), statistical analysis revealed a significantly greater proportion of linezolid-resistant isolates than delpazolid-resistant isolates within the MDR-TB group (P = 0.036). Seven (53.85%) of 13 linezolid-resistant isolates were found to harbor mutations within the three target genes. Additionally, 1 isolate exhibited an amino acid substitution (Arg126His) within the protein encoded by rplD that contributed to high-level resistance to linezolid (MIC of >16 mg/liter), compared to a delpazolid MIC of 0.25. In conclusion, in vitro susceptibility testing revealed that delpazolid antibacterial activity was comparable to that of linezolid. A novel mutation within rplD that endowed M. tuberculosis with linezolid, but not delpazolid, resistance was identified.

Roxithromycin potentiates the effects of chloroquine and mefloquine on multidrug-resistant Plasmodium falciparum in vitro

2007 ◽  
Vol 115 (4) ◽  
pp. 387-392 ◽  
Author(s):  
T.H. Min ◽  
M.F.M. Khairul ◽  
J.H. Low ◽  
C.H. Che Nasriyyah ◽  
A. Noor A’shikin ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistant

scholarly journals Effect of Fluorescent Dyes onIn Vitro-Differentiated, Late-Stage Plasmodium falciparum Gametocytes

2014 ◽  
Vol 58 (12) ◽  
pp. 7398-7404 ◽  
Author(s):  
Tamirat Gebru ◽  
Benjamin Mordmüller ◽  
Jana Held
Keyword(s):  
Plasmodium Falciparum ◽  
Late Stage ◽  
Fluorescent Dyes ◽  
Clinical Symptoms ◽  
Laboratory Strain ◽  
Clinical Isolates ◽  
Synthetic Dyes ◽  
Content Type ◽  
Highly Active

ABSTRACTPlasmodium falciparumgametocytes are not associated with clinical symptoms, but they are responsible for transmitting the pathogen to mosquitoes. Therefore, gametocytocidal interventions are important for malaria control and resistance containment. Currently available drugs and vaccines are not well suited for that purpose. Several dyes have potent antimicrobial activity, but their use against gametocytes has not been investigated systematically. The gametocytocidal activity of nine synthetic dyes and four control compounds was tested against stage V gametocytes of the laboratory strain 3D7 and three clinical isolates ofP. falciparumwith a bioluminescence assay. Five of the fluorescent dyes had submicromolar 50% inhibitory concentration (IC50) values against mature gametocytes. Three mitochondrial dyes, MitoRed, dihexyloxacarbocyanine iodide (DiOC6), and rhodamine B, were highly active (IC50s < 200 nM). MitoRed showed the highest activity against gametocytes, with IC50s of 70 nM against 3D7 and 120 to 210 nM against clinical isolates. All compounds were more active against the laboratory strain 3D7 than against clinical isolates. In particular, the endoperoxides artesunate and dihydroartemisinin showed a 10-fold higher activity against 3D7 than against clinical isolates. In contrast to all clinically used antimalarials, several fluorescent dyes had surprisingly highin vitroactivity against late-stage gametocytes. Since they also act against asexual blood stages, they shall be considered starting points for the development of new antimalarial lead compounds.

scholarly journals Plasmodium falciparum Line-Dependent Association ofIn VitroGrowth-Inhibitory Activity and Risk of Malaria

2012 ◽  
Vol 80 (5) ◽  
pp. 1900-1908 ◽  
Author(s):  
Josea Rono ◽  
Anna Färnert ◽  
Daniel Olsson ◽  
Faith Osier ◽  
Ingegerd Rooth ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Activity ◽  
Content Type ◽  
Phenotypic Differences ◽  
Erythrocyte Invasion ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Control Study

ABSTRACTPlasmodium falciparum's ability to invade erythrocytes is essential for its survival within the human host. Immune mechanisms that impair this ability are therefore expected to contribute to immunity against the parasite. Plasma of humans who are naturally exposed to malaria has been shown to have growth-inhibitory activity (GIA)in vitro. However, the importance of GIA in relation to protection from malaria has been unclear. In a case-control study nested within a longitudinally followed population in Tanzania, plasma samples collected at baseline from 171 individuals (55 cases and 116 age-matched controls) were assayed for GIA using threeP. falciparumlines (3D7, K1, and W2mef) chosen based on their erythrocyte invasion phenotypes. Distribution of GIA differed between the lines, with most samples inhibiting the growth of 3D7 and K1 and enhancing the growth of W2mef. GIA to 3D7 was associated with a reduced risk of malaria within 40 weeks of follow-up (odds ratio, 0.45; 95% confidence interval [CI], 0.21 to 0.96;P= 0.04), whereas GIA to K1 and W2mef was not. These results show that GIA, as well as its association with protection from malaria, is dependent on theP. falciparumline and can be explained by differences in erythrocyte invasion phenotypes between parasite lines. Our study contributes knowledge on the biological importance of growth inhibition and the potential influence ofP. falciparumerythrocyte invasion phenotypic differences on its relationship to protective immunity against malaria.

scholarly journals Efficacy of Biocides Used in the Modern Food Industry To Control Salmonella enterica, and Links between Biocide Tolerance and Resistance to Clinically Relevant Antimicrobial Compounds

2012 ◽  
Vol 78 (9) ◽  
pp. 3087-3097 ◽  
Author(s):  
Orla Condell ◽  
Carol Iversen ◽  
Shane Cooney ◽  
Karen A. Power ◽  
Ciara Walsh ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Food Industry ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Antimicrobial Compounds ◽  
Cross Tolerance ◽  
Content Type ◽  
Food Grade ◽  
High Level

ABSTRACTBiocides play an essential role in limiting the spread of infectious disease. The food industry is dependent on these agents, and their increasing use is a matter for concern. Specifically, the emergence of bacteria demonstrating increased tolerance to biocides, coupled with the potential for the development of a phenotype of cross-resistance to clinically important antimicrobial compounds, needs to be assessed. In this study, we investigated the tolerance of a collection of susceptible and multidrug-resistant (MDR)Salmonella entericastrains to a panel of seven commercially available food-grade biocide formulations. We explored their abilities to adapt to these formulations and their active biocidal agents, i.e., triclosan, chlorhexidine, hydrogen peroxide, and benzalkonium chloride, after sequential rounds ofin vitroselection. Finally, cross-tolerance of different categories of biocidal formulations, their active agents, and the potential for coselection of resistance to clinically important antibiotics were investigated. Six of seven food-grade biocide formulations were bactericidal at their recommended working concentrations. All showed a reduced activity against both surface-dried and biofilm cultures. A stable phenotype of tolerance to biocide formulations could not be selected. Upon exposure ofSalmonellastrains to an active biocidal compound, a high-level of tolerance was selected for a number ofSalmonellaserotypes. No cross-tolerance to the different biocidal agents or food-grade biocide formulations was observed. Most tolerant isolates displayed changes in their patterns of susceptibility to antimicrobial compounds. Food industry biocides are effective against planktonicSalmonella. When exposed to sublethal concentrations of individual active biocidal agents, tolerant isolates may emerge. This emergence was associated with changes in antimicrobial susceptibilities.

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