scholarly journals Selective sweeps and genetic lineages of Plasmodium falciparum multi-drug resistance (pfmdr1) gene in Kenya

2018 ◽  
Vol 17 (1) ◽  
Author(s):  
Peninah Muiruri ◽  
Denis W. Juma ◽  
Luicer A. Ingasia ◽  
Lorna J. Chebon ◽  
Benjamin Opot ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Multi Drug Resistance ◽  
Selective Sweeps ◽  
Pfmdr1 Gene ◽  
Genetic Lineages

scholarly journals A P-glycoprotein homologue of Plasmodium falciparum is localized on the digestive vacuole.

1991 ◽  
Vol 113 (5) ◽  
pp. 1033-1042 ◽  
Author(s):  
A F Cowman ◽  
S Karcz ◽  
D Galatis ◽  
J G Culvenor
Keyword(s):  
Plasmodium Falciparum ◽  
Gene Copy Number ◽  
Chloroquine Resistance ◽  
Gene Copy ◽  
Striking Similarity ◽  
Multi Drug Resistance ◽  
Digestive Vacuole ◽  
Pfmdr1 Gene ◽  
P Glycoprotein ◽  
Quantitative Immunoblotting

Resistance to chloroquine in Plasmodium falciparum bears a striking similarity to the multi-drug resistance (MDR) phenotype of mammalian tumor cells which is mediated by overexpression of P-glycoprotein. We show here that the P. falciparum homologue of the P-glycoprotein (Pgh1) is a 160,000-D protein that is expressed throughout the asexual erythrocytic life cycle of the parasite. Quantitative immunoblotting analysis has shown that the protein is expressed at approximately equal levels in chloroquine resistant and sensitive isolates suggesting that overexpression of Pgh1 is not essential for chloroquine resistance. The chloroquine-resistant cloned line FAC8 however, does express approximately threefold more Pgh1 protein than other isolates which is most likely because of the increased pfmdr1 gene copy number present in this isolate. Immunofluorescence and immunoelectron microscopy has demonstrated that Pgh1 is localized on the membrane of the digestive vacuole of mature parasites. This subcellular localization suggests that Pgh1 may modulate intracellular chloroquine concentrations and has important implications for the normal physiological function of this protein.

scholarly journals P. falciparum PfATP4 Multi-Drug Resistance Resistance to KAE609 (Cipargamin) is Present in Africa

2018 ◽  
Author(s):  
James McCulloch
Keyword(s):  
Drug Resistance ◽  
Clinical Trials ◽  
Plasmodium Falciparum ◽  
Resistance Mutation ◽  
Drug Resistance Mutation ◽  
Blood Stage ◽  
Policy Implications ◽  
Multi Drug Resistance ◽  
Drug Resistant ◽  
Important Policy

AbstractThe PfATP4 (PF3D7 1211900) multi-drug resistance mutation G223R is found in Africa by genetically analyzing 2640 worldwide Plasmodium falciparum blood stage isolates (the MalariaGen Pf3k resource). This mutation confers an approximate 8 fold [4] increase in the PfATP4 IC50 of Spiroindolones (KAE609 & KAE678) [14],[16],[4],[10] and Aminopyrazoles (GNF-Pf4492) [4]. It is postulated that the G223R mutation may be a consequence of the drug resistant Southeast Asian Dd2 genotype becoming more dominant in Africa [3]. The presence of this mutation has important policy implications for the eventual general deployment of the Spiroindolone KAE609 (Cipargamin) which is currently undergoing stage 2 clinical trials.

scholarly journals Plasmodium falciparum Multidrug Resistance Proteins (pfMRPs)

2021 ◽  
Vol 12 ◽  
Author(s):  
José Pedro Gil ◽  
Cláudia Fançony
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Multi Drug Resistance ◽  
Multidrug Resistance Proteins ◽  
Resistance Proteins ◽  
Diverse Groups ◽  
Endogenous Substances

The capacity of the lethal Plasmodium falciparum parasite to develop resistance against anti-malarial drugs represents a central challenge in the global control and elimination of malaria. Historically, the action of drug transporters is known to play a pivotal role in the capacity of the parasite to evade drug action. MRPs (Multidrug Resistance Protein) are known in many phylogenetically diverse groups to be related to drug resistance by being able to handle a large range of substrates, including important endogenous substances as glutathione and its conjugates. P. falciparum MRPs are associated with in vivo and in vitro altered drug response, and might be important factors for the development of multi-drug resistance phenotypes, a latent possibility in the present, and future, combination therapy environment. Information on P. falciparum MRPs is scattered in the literature, with no specialized review available. We herein address this issue by reviewing the present state of knowledge.

scholarly journals Polymorphism Analysis of pfmdr1 Gene in Plasmodium falciparum Isolates 11 Years Post-adoption of Artemisinin-based Combination Therapy in Saudi Arabia

2021 ◽  
Author(s):  
Hesham M. Al-Mekhlafi ◽  
Aymen M. Madkhali ◽  
Ahmed A. Abdulhaq ◽  
Wahib M. Atroosh ◽  
Ahmad Hassn Ghzwani ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Saudi Arabia ◽  
Combination Therapy ◽  
Point Mutations ◽  
Multi Drug Resistance ◽  
Polymorphism Analysis ◽  
Wild Allele ◽  
High Prevalence ◽  
Parasitaemia Level

Abstract A total of 227 Plasmodium falciparum isolates from Jazan region, southwestern Saudi Arabia were amplified for the P. falciparum multi-drug resistance 1 (pfmdr1) gene to detect point mutations 11 years after the introduction of artemisinin-based combination therapy (ACT) in Saudi Arabia. The pfmdr1 86Y mutation was found in 11.5% (26/227) of the isolates while the N86 wild allele was detected in 88.5%. Moreover, 184F point mutations dominated (86.3%) the instances of pfmdr1 polymorphism while no mutation was observed at codons 1034, 1042 and 1246. Three pfmdr1 haplotypes were identified, NFSND (74.9%), NYSND (13.7%) and YFSND (11.4%). Associations of the prevalence of 86Y mutation and YFSND haplotype with participants’ nationality, residency and parasitaemia level were found to be significant (P < 0.05). The findings revealed significant decline in the prevalence of the pfmdr1 86Y mutation in P. falciparum isolates from Jazan region over a decade after the implementation of ACT treatment. Moreover, the high prevalence of the NFSND haplotype might be indicative of the potential emergence of CQ-sensitive but artemether-lumefantrine-resistant P. falciparum strains since the adoption of ACT. Therefore, continuous monitoring of the molecular markers of antimalarial drug resistance in Jazan region is highly recommended.

Local differentiation in Plasmodium falciparum drug resistance genes in Sudan

Parasitology ◽  
2003 ◽  
Vol 126 (5) ◽  
pp. 391-400 ◽  
Author(s):  
A. A. ABDEL-MUHSIN ◽  
M. J. MACKINNON ◽  
P. AWADALLA ◽  
E. ALI ◽  
S. SULEIMAN ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Population Structure ◽  
Resistance Genes ◽  
Microsatellite Loci ◽  
Balancing Selection ◽  
Dry Season ◽  
Chloroquine Resistance ◽  
Multi Drug Resistance ◽  
Eastern Region

Studies of population genetic structure of parasites can be used to infer which parasite genes are under selection. Here, the population structure of 4 genes associated with drug resistance of Plasmodium falciparum (the chloroquine resistance transporter, pfcrt, dihydrofolate reductase, dhfr, dihydropteroate synthase, dhps, and multi-drug resistance, pfmdr-1) were examined in parasite populations in 3 villages in eastern Sudan and in an urban area of Khartoum, the capital. In order to differentiate the effects of drug selection from neutral influences on population structure, parasites were also genotyped for 3 putatively neutral microsatellite loci (polyα, TA81 and pfg377), and for 2 antigenic loci that are either under balancing selection or neutral, merozoite surface protein 1 and 2, (MSP-1 and MSP-2). Cross-sectional surveys were carried out during the peak transmission (wet) season and in the ensuing dry season. No significant variation in frequencies of MSP-1 and MSP-2 alleles was seen among villages in the eastern region and between the villages and Khartoum, nor between the wet and dry season. However, the drug resistance genes, pfmdr-1, pfcrt and dhfr and to a lesser extent the microsatellite loci showed high FST values when comparing villages with Khartoum, indicating strong geographical differentiation at these loci. Moreover, variation in frequencies of the drug resistance genes, pfmdr-1, pfcrt and dhfr, was observed between the wet and dry season. These differences most probably reflect the variation in drug pressure between each region, and in drug usage between the wet and dry season in a given region.

scholarly journals Analyzing the Essential Proteins Set of Plasmodium Falciparum PF3D7 for Novel Drug Targets Identification Against Malaria

2021 ◽  
Author(s):  
Fawad Ali ◽  
Hira Wali ◽  
Saadia Jan ◽  
Muneeba Aslam ◽  
Imtiaz Ahmad ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Protein Interactions ◽  
Drug Targets ◽  
Human Life ◽  
Multi Drug Resistance ◽  
Essential Proteins ◽  
Human Host

Abstract Background: Plasmodium falciparum is an obligate intracellular parasite of humans that causes malaria. P. falciparum is a major public health threat to human life responsible for high mortality. Currently, the risk of multi-drug resistance of P. falciparum is rapidly increasing. There is a need to address new anti-malarial therapeutics strategies to combat the drug-resistance threat.Methods: We retrieved the P. falciparum essential proteins from the recently published studies. Pathogen essential proteins were initially scanned against human host and its gut microbiome proteome sets by comparative proteomics analyses. The human host non-homologs essential proteins of P. falciparum were additionally analyzed for druggability potential via in silico methods to possibly identify novel therapeutic targets.Results: The analyses identified six P. falciparum essential and human host non-homolog proteins that follow the key druggability features. These druggable targets have not catalogued so far in the Drugbank repository. These prioritized proteins seem novel and promising drug targets against P. falciparum due to their key protein-protein interactions features in pathogen-specific biological pathways and to hold appropriate drug-like molecule binding pockets. Conclusion: The prioritized protein targets may worthy to test in malarial drug discovery program to overcome the anti-malarial resistance issues. The in-vitro and in-vivo studies might be promising for additional validation of these prioritized lists of drug targets against malaria.

scholarly journals Polymorphism analysis of pfmdr1 gene in Plasmodium falciparum isolates 11 years post-adoption of artemisinin-based combination therapy in Saudi Arabia

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Hesham M. Al-Mekhlafi ◽  
Aymen M. Madkhali ◽  
Ahmed A. Abdulhaq ◽  
Wahib M. Atroosh ◽  
Ahmad Hassn Ghzwani ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Saudi Arabia ◽  
Combination Therapy ◽  
Point Mutations ◽  
Multi Drug Resistance ◽  
Polymorphism Analysis ◽  
Wild Allele ◽  
High Prevalence ◽  
Parasitaemia Level

AbstractA total of 227 Plasmodium falciparum isolates from Jazan region, southwestern Saudi Arabia were amplified for the P. falciparum multi-drug resistance 1 (pfmdr1) gene to detect point mutations 11 years after the introduction of artemisinin-based combination therapy (ACT) in Saudi Arabia. The pfmdr1 86Y mutation was found in 11.5% (26/227) of the isolates while the N86 wild allele was detected in 88.5%. Moreover, 184F point mutations dominated (86.3%) the instances of pfmdr1 polymorphism while no mutation was observed at codons 1034, 1042 and 1246. Three pfmdr1 haplotypes were identified, NFSND (74.9%), NYSND (13.7%) and YFSND (11.4%). Associations of the prevalence of 86Y mutation and YFSND haplotype with participants’ nationality, residency and parasitaemia level were found to be significant (P < 0.05). The findings revealed significant decline in the prevalence of the pfmdr1 86Y mutation in P. falciparum isolates from Jazan region over a decade after the implementation of ACT treatment. Moreover, the high prevalence of the NFSND haplotype might be indicative of the potential emergence of CQ-sensitive but artemether-lumefantrine-resistant P. falciparum strains since the adoption of ACT. Therefore, continuous monitoring of the molecular markers of antimalarial drug resistance in Jazan region is highly recommended.

scholarly journals Analysing the essential proteins set of Plasmodium falciparum PF3D7 for novel drug targets identification against malaria

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Fawad Ali ◽  
Hira Wali ◽  
Saadia Jan ◽  
Asad Zia ◽  
Muneeba Aslam ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Virtual Screening ◽  
Drug Targets ◽  
Human Life ◽  
Multi Drug Resistance ◽  
Essential Proteins ◽  
Human Host

Abstract Background Plasmodium falciparum is an obligate intracellular parasite of humans that causes malaria. Falciparum malaria is a major public health threat to human life responsible for high mortality. Currently, the risk of multi-drug resistance of P. falciparum is rapidly increasing. There is a need to address new anti-malarial therapeutics strategies to combat the drug-resistance threat. Methods The P. falciparum essential proteins were retrieved from the recently published studies. These proteins were initially scanned against human host and its gut microbiome proteome sets by comparative proteomics analyses. The human host non-homologs essential proteins of P. falciparum were additionally analysed for druggability potential via in silico methods to possibly identify novel therapeutic targets. Finally, the PfAp4AH target was prioritized for pharmacophore modelling based virtual screening and molecular docking analyses to identify potent inhibitors from drug-like compounds databases. Results The analyses identified six P. falciparum essential and human host non-homolog proteins that follow the key druggability features. These druggable targets have not been catalogued so far in the Drugbank repository. These prioritized proteins seem novel and promising drug targets against P. falciparum due to their key protein–protein interactions features in pathogen-specific biological pathways and to hold appropriate drug-like molecule binding pockets. The pharmacophore features based virtual screening of Pharmit resource predicted a lead compound i.e. MolPort-045–917-542 as a promising inhibitor of PfAp4AH among prioritized targets. Conclusion The prioritized protein targets may worthy to test in malarial drug discovery programme to overcome the anti-malarial resistance issues. The in-vitro and in-vivo studies might be promising for additional validation of these prioritized lists of drug targets against malaria.

scholarly journals Prevalence of pfk13 and pfmdr1 polymorphisms in Bounkiling, Southern Senegal

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0249357
Author(s):  
Ambroise Ahouidi ◽  
Rafael Oliveira ◽  
Lis Lobo ◽  
Cyrille Diedhiou ◽  
Souleymane Mboup ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Pcr Amplification ◽  
Parasite Clearance ◽  
Dried Blood Spots ◽  
Multi Drug Resistance ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Multidrug Resistance Gene ◽  
Filter Papers

Background Delayed Plasmodium falciparum parasite clearance has been associated with Single Nucleotide Polymorphisms (SNPs) in the kelch protein propeller domain (coded by pfk13 gene). SNPs in the Plasmodium falciparum multidrug resistance gene 1 (pfmdr1) are associated with multi-drug resistance including the combination artemether-lumefantrine. To our knowledge, this is the first work providing information on the prevalence of k13-propeller and pfmdr1 mutations from Sédhiou, a region in the south of Senegal. Methods 147 dried blood spots on filter papers were collected from symptomatic patients attending a hospital located in Bounkiling City, Sédhiou Region, Southern Senegal. All samples were collected between 2015–2017 during the malaria transmission season. Specific regions of the gene pfk13 and pfmdr1 were analyzed using PCR amplification and Sanger sequencing. Results The majority of parasites (92.9%) harboured the pfk13 wild type sequence and 6 samples harboured synonymous changes. Regarding pfmdr1, wild-type alleles represented the majority except at codon 184. Overall, prevalence of 86Y was 11.9%, 184F was 56.3% and 1246Y was 1.5%. The mutant allele 184F decreased from 73.7% in 2015 to 40.7% in 2017. The prevalence of haplotype NFD decreased from 71.4% in 2015 to 20.8% in 2017. Conclusions This study provides the first description of pfk13 and pfmdr1 genes variations in Bounkiling, a city in the Sédhiou Region of Senegal, contributing to closing the gap of information on anti-malaria drug resistance molecular markers in southern Senegal.

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