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 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 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 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 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 The Structure of the Cysteine-Rich Domain of Plasmodium falciparum P113 Identifies the Location of the RH5 Binding Site

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Ivan Campeotto ◽  
Francis Galaway ◽  
Shahid Mehmood ◽  
Lea K. Barfod ◽  
Doris Quinkert ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Binding Site ◽  
Structural Information ◽  
Blood Stage ◽  
Site Directed Mutagenesis ◽  
Effective Vaccine ◽  
Binding Region ◽  
Fab Fragment ◽  
Content Type ◽  
Blood Stage Malaria

ABSTRACT Plasmodium falciparum RH5 is a secreted parasite ligand that is essential for erythrocyte invasion through direct interaction with the host erythrocyte receptor basigin. RH5 forms a tripartite complex with two other secreted parasite proteins, CyRPA and RIPR, and is tethered to the surface of the parasite through membrane-anchored P113. Antibodies against RH5, CyRPA, and RIPR can inhibit parasite invasion, suggesting that vaccines containing these three components have the potential to prevent blood-stage malaria. To further explore the role of the P113-RH5 interaction, we selected monoclonal antibodies against P113 that were either inhibitory or noninhibitory for RH5 binding. Using a Fab fragment as a crystallization chaperone, we determined the crystal structure of the RH5 binding region of P113 and showed that it is composed of two domains with structural similarities to rhamnose-binding lectins. We identified the RH5 binding site on P113 by using a combination of hydrogen-deuterium exchange mass spectrometry and site-directed mutagenesis. We found that a monoclonal antibody to P113 that bound to this interface and inhibited the RH5-P113 interaction did not inhibit parasite blood-stage growth. These findings provide further structural information on the protein interactions of RH5 and will be helpful in guiding the development of blood-stage malaria vaccines that target RH5. IMPORTANCE Malaria is a deadly infectious disease primarily caused by the parasite Plasmodium falciparum. It remains a major global health problem, and there is no highly effective vaccine. A parasite protein called RH5 is centrally involved in the invasion of host red blood cells, making it—and the other parasite proteins it interacts with—promising vaccine targets. We recently identified a protein called P113 that binds RH5, suggesting that it anchors RH5 to the parasite surface. In this paper, we use structural biology to locate and characterize the RH5 binding region on P113. These findings will be important to guide the development of new antimalarial vaccines to ultimately prevent this disease, which affects some of the poorest people on the planet.

scholarly journals Kenyan Plasmodium falciparum Field Isolates: Correlation between Pyrimethamine and Chlorcycloguanil Activity In Vitro and Point Mutations in the Dihydrofolate Reductase Domain

1998 ◽  
Vol 42 (1) ◽  
pp. 164-169 ◽  
Author(s):  
A. Nzila-Mounda ◽  
E. K. Mberu ◽  
C. H. Sibley ◽  
C. V. Plowe ◽  
P. A. Winstanley ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Dihydrofolate Reductase ◽  
Drug Response ◽  
Point Mutations ◽  
Distinct Group ◽  
Wild Type ◽  
Field Isolates ◽  
Vitro Data ◽  
In Vitro Data

ABSTRACT Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC50s) for PM and CCG (P< 0.01) and their DHFR genotypes. The first group consists of wild-type isolates with mean PM and CCG IC50s of 3.71 ± 6.94 and 0.24 ± 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC50s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC50s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease (P < 0.01) of SD and DDS susceptibility in these triple mutants. Our data show that more than 92% of Kenyan field isolates have undergone at least one point mutation associated with a decrease in PM activity. These findings are of great concern because they may indicate imminent PM-SD failure, and there is no affordable antimalarial drug to replace PM-SD (Fansidar).

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
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