scholarly journals Molecular Mechanisms of Drug Resistance in Plasmodium falciparum Malaria

2020 ◽  
Vol 74 (1) ◽  
pp. 431-454
Author(s):  
Kathryn J. Wicht ◽  
Sachel Mok ◽  
David A. Fidock
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Mechanisms ◽  
Artemisinin Resistance ◽  
Plasmodium Falciparum Malaria ◽  
Drug Binding ◽  
Chloroquine Resistance ◽  
Digestive Vacuole ◽  
Vacuole Membrane ◽  
Chloroquine Resistance Transporter ◽  
Antimalarial Resistance

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.

scholarly journals No Plasmodium falciparum Chloroquine Resistance Transporter and Artemisinin Resistance Mutations, Haiti

2018 ◽  
Vol 24 (11) ◽  
pp. 2124-2126 ◽  
Author(s):  
Jeanne P. Vincent ◽  
Kanako Komaki-Yasuda ◽  
Alexandre V. Existe ◽  
Jacques Boncy ◽  
Shigeyuki Kano
Keyword(s):  
Plasmodium Falciparum ◽  
Artemisinin Resistance ◽  
Chloroquine Resistance ◽  
Resistance Mutations ◽  
Chloroquine Resistance Transporter

scholarly journals Mutation in the Plasmodium falciparum CRT Protein Determines the Stereospecific Activity of Antimalarial Cinchona Alkaloids

2012 ◽  
Vol 56 (10) ◽  
pp. 5356-5364 ◽  
Author(s):  
Carol E. Griffin ◽  
Jonathan M. Hoke ◽  
Upeka Samarakoon ◽  
Junhui Duan ◽  
Jianbing Mu ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Cinchona Alkaloids ◽  
Chloroquine Resistance ◽  
Digestive Vacuole ◽  
Content Type ◽  
Chloroquine Resistance Transporter ◽  
Clonal Lines

ABSTRACTTheCinchonaalkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (−)-quinine and (+)-quinidine. The potency of (+)-isomers is greater than the (−)-isomersin vitroandin vivoagainstPlasmodium falciparummalaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparumchloroquine resistance transporter), reversed the normal potency order of quinine and quinidine towardP. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured thein vitrosusceptibility of eight clonal lines ofP. falciparumderived from the 106/1 strain, each containing a uniquepfcrtallele, to fourCinchonastereoisomer pairs: quinine and quinidine; cinchonidine and cinchonine; hydroquinine and hydroquinidine; 9-epiquinine and 9-epiquinidine. Stereospecific potency of theCinchonaalkaloids was associated with changes in charge and hydrophobicity of mutable PfCRT amino acids. In isogenic chloroquine-resistant lines, the IC50ratio of (−)/(+) CA pairs correlated with side chain hydrophobicity of the position 76 residue. Second-site PfCRT mutations negated the K76I stereospecific effects: charge-change mutations C72R or Q352K/R restored potency patterns similar to the parent K76 line, while V369F increased susceptibility to the alkaloids and nullified stereospecific differences between alkaloid pairs. Interactions between key residues of the PfCRT channel/transporter with (−) and (+) alkaloids are stereospecifically determined, suggesting that PfCRT binding plays an important role in the antimalarial activity of quinine and otherCinchonaalkaloids.

scholarly journals Polymorphism Analysis of pfmdr1 and pfcrt from Plasmodium falciparum Isolates in Northwestern Nigeria Revealed the Major Markers Associated with Antimalarial Resistance

Diseases ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 6
Author(s):  
Ruqayya Adam ◽  
Muhammad M. Mukhtar ◽  
Umar F. Abubakar ◽  
Hajara A. Damudi ◽  
Abdullahi Muhammad ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Management Strategies ◽  
Haplotype Diversity ◽  
Resistance Management ◽  
Chloroquine Resistance ◽  
Polymorphism Analysis ◽  
Resistance Mutations ◽  
Chloroquine Resistance Transporter ◽  
Antimalarial Resistance ◽  
Additional Sequence

Suspicion of failure in the effectiveness of artemisinin-based combination therapies (currently the first-line treatment of malaria, worldwide) is leading to the unofficial use of alternative antimalarials, including chloroquine and sulfadoxine/pyrimethamine, across northern Nigeria. To facilitate evidence-based resistance management, antimalarial resistance mutations were investigated in Plasmodium falciparum multidrug resistance-1 (pfmdr1) and chloroquine resistance transporter (pfcrt), in isolates from Kano, northwestern Nigeria. Out of the 88 samples genotyped for pfmdr1N86Y mutation using PCR/restriction fragment length polymorphism, one sample contained the 86Y mutation (86Yfrequency = 1.14%). The analysis of 610 bp fragments of pfmdr1 from 16 isolates revealed two polymorphic sites and low haplotype diversity (Hd = 0.492), with only 86 Y mutations in one isolate, and 184 F replacements in five isolates (184Ffrequency = 31.25%). The analysis of 267 bp fragments of pfcrt isolates revealed high polymorphism (Hd = 0.719), with six haplotypes and seven non-synonymous polymorphic sites. Eleven isolates (61.11%) were chloroquine-resistant, CQR (C72V73I74E75T76 haplotype), two of which had an additional mutation, D57E. An additional sequence was CQR, but of the C72V73M74E75T76 haplotype, while the rest of the sequences (33.33%) were chloroquine susceptible (C72V73M74N75K76 haplotype). The findings of these well characterized resistance markers should be considered when designing resistance management strategies in the northwestern Nigeria.

scholarly journals Efficacy of Artesunate-Amodiaquine and Artemether-Lumefantrine for Uncomplicated Plasmodium Falciparum Malaria in Madagascar, 2018

2021 ◽  
Author(s):  
Catherine M. Dentinger ◽  
Tovonahary Angelo Rakotomanga ◽  
Antsa Rakotondrandriana ◽  
Arinomenjanahary Rakotoarisoa ◽  
Marie Ange Rason ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Markers ◽  
Artemisinin Resistance ◽  
Plasmodium Falciparum Malaria ◽  
Outcome Data ◽  
World Health ◽  
Antimalarial Resistance ◽  
Health Organization ◽  
Uncomplicated Plasmodium Falciparum Malaria

Abstract Background: Since 2005, artemisinin-based combination therapy (ACT) has been recommended to treat uncomplicated Plasmodium falciparum malaria in Madagascar. Artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are the first- and second-line treatments, respectively. A therapeutic efficacy study was conducted to assess ACT efficacy and molecular markers of antimalarial resistance.Methods: Children aged six months through 14 years with uncomplicated P. falciparum malaria and a parasitemia of 1,000—100,000 parasites/µl determined by microscopy were enrolled from May—September 2018 in a 28-day in vivo trial using the 2009 World Health Organization protocol for monitoring antimalarial efficacy. Participants from two communes, Ankazomborona (tropical, northwest) and Matanga (equatorial, southeast), were randomly assigned to ASAQ or AL arms. PCR correction was achieved by genotyping seven neutral microsatellites in paired pre- and post-treatment samples. Genotyping assays for molecular markers of resistance in the pfk13, pfcrt, and pfmdr1 genes were conducted.Results: Of 344 patients enrolled, 164/170 (96%) receiving ASAQ and 170/174 (98%) receiving AL completed the study. For ASAQ, the day-28 cumulative PCR-uncorrected efficacy was 100% (95% CI 100–100) and 95% (95% CI 91–100) for Ankazomborona and Matanga, respectively; for AL, it was 99% (95% CI 97–100) in Ankazomborona and 84% (95% CI 76–92) in Matanga. The day-28 cumulative PCR-corrected efficacy for ASAQ was 100% (95% CI 100–100) and 97% (95% CI 94–100%) for Ankazomborona and Matanga, respectively; for AL, it was 100% (95% CI 99–100) in Ankazomborona and 96% (95% CI 91–100) in Matanga. Of 83 successfully sequenced samples for pfk13, no mutations associated with artemisinin resistance were observed. A majority of successfully sequenced samples for pfmdr1 carried either the NFD or NYD haplotypes corresponding to codons 86, 184, and 1246. Of 82 successfully sequenced samples for pfcrt, all were wild type at codons 72–76. Conclusion: PCR-corrected analysis indicated that ASAQ and AL have therapeutic efficacies above the 90% WHO acceptable cut-off. We did not observe any genetic evidence of resistance to artemisinin, consistent with the clinical outcome data. However, the most common pfmdr1 haplotypes were NYD and NFD, previously associated with tolerance to lumefantrine.

scholarly journals Differential Drug Efflux or Accumulation Does Not Explain Variation in the Chloroquine Response of Plasmodium falciparum Strains Expressing the Same Isoform of Mutant PfCRT

2011 ◽  
Vol 55 (5) ◽  
pp. 2310-2318 ◽  
Author(s):  
Adele M. Lehane ◽  
Donelly A. van Schalkwyk ◽  
Stephanie G. Valderramos ◽  
David A. Fidock ◽  
Kiaran Kirk
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Concentration ◽  
Chloroquine Resistance ◽  
Mutant Form ◽  
Digestive Vacuole ◽  
Biochemical Basis ◽  
Content Type ◽  
Chloroquine Resistance Transporter ◽  
The Difference ◽  
Mutant Forms

ABSTRACTMutant forms of thePlasmodium falciparumchloroquine resistance transporter (PfCRT) mediate chloroquine resistance by effluxing the drug from the parasite's digestive vacuole, the acidic organelle in which chloroquine exerts its parasiticidal effect. However, different parasites bearing the same mutant form of PfCRT can vary substantially in their chloroquine susceptibility. Here, we have investigated the biochemical basis for the difference in chloroquine response among transfectant parasite lines having different genetic backgrounds but bearing the same mutant form of PfCRT. Despite showing significant differences in their chloroquine susceptibility, all lines with the mutant PfCRT showed a similar chloroquine-induced H+leak from the digestive vacuole, indicative of similar rates of PfCRT-mediated chloroquine efflux. Furthermore, all lines showed similarly reduced levels of drug accumulation. Factors other than chloroquine efflux and accumulation therefore influence the susceptibility to this drug in parasites expressing mutant PfCRT. Furthermore, in some but not all strains bearing mutant PfCRT, the 50% inhibitory concentration (IC50) for chloroquine and the degree of resistance compared to that of recombinant control parasites varied with the length of the parasite growth assays. In these parasites, the 50% inhibitory concentration for chloroquine measured in 72- or 96-h assays was significantly lower than that measured in 48-h assays. This highlights the importance of considering the first- and second-cycle activities of chloroquine in future studies of parasite susceptibility to this drug.

scholarly journals A Computational Study of Molecular Mechanism of Chloroquine Resistance by Chloroquine Resistance Transporter Protein of Plasmodium falciparum via Molecular Modeling and Molecular Simulations

Physchem ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 232-242
Author(s):  
Chandan Patel ◽  
Dipankar Roy
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Modeling ◽  
Molecular Mechanism ◽  
Computational Study ◽  
Chloroquine Resistance ◽  
Drug Efflux ◽  
Digestive Vacuole ◽  
Transporter Protein ◽  
Chloroquine Resistance Transporter ◽  
Protonated Forms

The molecular mechanism of chloroquine resistance by the chloroquine resistance transporter protein of Plasmodium sp. is explored using molecular modeling and computational methods. The key mutation, lysine(K)-76 to threonine(T) (LYS76THR) in the transporter protein pertains to increased recognition of the protonated forms of the antimalarial drug. Such enhanced affinity can promote drug efflux from host digestive vacuole, rendering aminoquinoline-based treatment ineffective.

scholarly journals Predictors of treatment failures of plasmodium falciparum malaria in Vietnam: a 4-year single‐centre retrospective study

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Minh Cuong Duong ◽  
Oanh Kieu Nguyet Pham ◽  
Phong Thanh Nguyen ◽  
Van Vinh Chau Nguyen ◽  
Phu Hoan Nguyen
Keyword(s):  
Plasmodium Falciparum ◽  
Treatment Failure ◽  
Severe Malaria ◽  
Falciparum Malaria ◽  
Control Strategies ◽  
Artemisinin Resistance ◽  
Plasmodium Falciparum Malaria ◽  
Molecular Technique ◽  
Drug Resistant ◽  
Public Health Burden

Abstract Background Drug-resistant falciparum malaria is an increasing public health burden. This study examined the magnitude of Plasmodium falciparum infection and the patterns and predictors of treatment failure in Vietnam. Methods Medical records of all 443 patients with malaria infection admitted to the Hospital for Tropical Diseases between January 2015 and December 2018 were used to extract information on demographics, risk factors, symptoms, laboratory tests, treatment, and outcome. Results More than half (59.8%, 265/443, CI 55.1–64.4%) of patients acquired Plasmodium falciparum infection of whom 21.9% (58/265, CI 17.1–27.4%) had severe malaria, while 7.2% (19/265, CI 4.6–10.9%) and 19.2% (51/265, CI 14.7–24.5%) developed early treatment failure (ETF) and late treatment failure (LTF) respectively. Among 58 patients with severe malaria, 14 (24.1%) acquired infection in regions where artemisinin resistance has been documented including Binh Phuoc (11 patients), Dak Nong (2 patients) and Gia Lai (1 patient). Under treatment with intravenous artesunate, the median (IQR) parasite half-life of 11 patients coming from Binh Phuoc was 3 h (2.3 to 8.3 h), two patients coming from Dak Nong was 2.8 and 5.7 h, and a patient coming from Gia Lai was 6.5 h. Most patients (98.5%, 261/265) recovered completely. Four patients with severe malaria died. Severe malaria was statistically associated with receiving treatment at previous hospitals (P < 0.001), hepatomegaly (P < 0.001) and number of inpatient days (P < 0.001). Having severe malaria was a predictor of ETF (AOR 6.96, CI 2.55–19.02, P < 0.001). No predictor of LTF was identified. Conclusions Plasmodium falciparum remains the prevalent malaria parasite. Despite low mortality rate, severe malaria is not rare and is a significant predictor of ETF. To reduce the risk for ETF, studies are needed to examine the effectiveness of combination therapy including parenteral artesunate and a parenteral partner drug for severe malaria. The study alerts the possibility of drug-resistant malaria in Africa and other areas in Vietnam, which are known as non-endemic areas of anti-malarial drug resistance. A more comprehensive study using molecular technique in these regions is required to completely understand the magnitude of drug-resistant malaria and to design appropriate control strategies.

scholarly journals Therapeutic efficacy of artemether–lumefantrine and artesunate–amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Mali, 2015–2016

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Youssouf Diarra ◽  
Oumar Koné ◽  
Lansana Sangaré ◽  
Lassina Doumbia ◽  
Dade Bouye Ben Haidara ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Uncomplicated Malaria ◽  
Artemisinin Resistance ◽  
National Malaria Control Programme ◽  
Plasmodium Falciparum Malaria ◽  
Control Programme ◽  
Malaria Control Programme ◽  
Pre Treatment ◽  
Better Than

Abstract Background The current first-line treatments for uncomplicated malaria recommended by the National Malaria Control Programme in Mali are artemether–lumefantrine (AL) and artesunate–amodiaquine (ASAQ). From 2015 to 2016, an in vivo study was carried out to assess the clinical and parasitological responses to AL and ASAQ in Sélingué, Mali. Methods Children between 6 and 59 months of age with uncomplicated Plasmodium falciparum infection and 2000–200,000 asexual parasites/μL of blood were enrolled, randomly assigned to either AL or ASAQ, and followed up for 42 days. Uncorrected and PCR-corrected efficacy results at days 28 and 42. were calculated. Known markers of resistance in the Pfk13, Pfmdr1, and Pfcrt genes were assessed using Sanger sequencing. Results A total of 449 patients were enrolled: 225 in the AL group and 224 in the ASAQ group. Uncorrected efficacy at day 28 was 83.4% (95% CI 78.5–88.4%) in the AL arm and 93.1% (95% CI 89.7–96.5%) in the ASAQ arm. The per protocol PCR-corrected efficacy at day 28 was 91.0% (86.0–95.9%) in the AL arm and 97.1% (93.6–100%) in the ASAQ arm. ASAQ was significantly (p < 0.05) better than AL for each of the aforementioned efficacy outcomes. No mutations associated with artemisinin resistance were identified in the Pfk13 gene. Overall, for Pfmdr1, the N86 allele and the NFD haplotype were the most common. The NFD haplotype was significantly more prevalent in the post-treatment than in the pre-treatment isolates in the AL arm (p < 0.01) but not in the ASAQ arm. For Pfcrt, the CVIET haplotype was the most common. Conclusions The findings indicate that both AL and ASAQ remain effective for the treatment of uncomplicated malaria in Sélingué, Mali.

scholarly journals The impact of HIV-associated immunosuppression on the Plasmodium falciparum chloroquine resistance transporter gene (PfCRT) of HIV patients in Akure, Nigeria

2020 ◽  
Vol 44 (1) ◽  
Author(s):  
Iyabo Adepeju Simon-Oke ◽  
Adeola Olanireti Ade-Alao ◽  
Foluso Ologundudu
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Prevalence ◽  
Cd4 Count ◽  
Chloroquine Resistance ◽  
Hiv Care ◽  
Transporter Gene ◽  
Hiv Patients ◽  
Chloroquine Resistance Transporter ◽  
Hiv Test ◽  
Low Prevalence

Abstract Background The study evaluated the prevalence of malaria and Plasmodium falciparum chloroquine resistance transporter gene (PfCRT) in HIV patients attending Specialist Hospital, Akure. This study was carried out between April and June 2019. Three hundred and seventeen (317) patients attending the antiretroviral clinic (ART) were involved, out of which 89 (28.08%) were males and 228 (71.92%) were females. HIV test was done using the Unigold® HIV test kit, malaria test was done using thick and thin blood smear, CD4 test was done using the Partec® CD4 counter and PCR was used to detect the presence of plasmodium falciparum mutant gene. The data obtained from this analysis was subjected to Pearson’s Chi-square test. Results The overall result showed low prevalence of malaria (23.03%) in the sampled patients. Highest malaria prevalence (31.0%) was recorded in HIV patients with CD4 count between 200–500 cells/μl of blood, with the males recording 24.7% malaria prevalence. The age group 20–29 years recorded the highest prevalence of 27.3%. A higher prevalence 91.1% of PfCRT gene in HIV-positive and (40.0%) in HIV-negative patients was recorded with 100% prevalence in patients with CD4 count ≤ 200. This shows that the low prevalence of malaria recorded in this study could be credited to good health-seeking attitude of HIV patients and the upscale of HIV care and treatment centres. Conclusion The high prevalence of PfCRT gene shows that treatment of malaria with chloroquine is still being practised despite the availability of artemisinin-based combination therapy (ACTs) as the recommended regimen for malaria treatment.

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