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artemisinin resistance

Not Open Access | C-terminal aromatic residue of Plasmodium ferredoxin important for the interaction with ferredoxin:NADP(H) oxidoreductase: possible involvement for artemisinin resistance of human malaria parasites

June 1, 2020 - 16:48 -- NOT Open Access
Author(s): 
Kimata-Ariga Y, Sakamoto A, Kamatani M, Saitoh T, Hase T
Reference: 
J Biochem. 2020 May 29:mvaa060

The malaria parasite (Plasmodium sp.) contains a plastid-derived organelle called the apicoplast, which is essential for the growth of the parasite. In this organelle, a redox system comprising plant-type ferredoxin (Fd) and Fd:NADP(H) oxidoreductase (FNR) supplies reducing power for the crucial metabolic pathways. Electron transfer between P. falciparum Fd (PfFd) and FNR (PfFNR) is performed with higher affinity and specificity than those of plant Fd and FNR. We investigated the structural basis for such superior protein-protein interaction by focusing on the Plasumodium-specific regions of PfFd.

Local emergence in Amazonia of Plasmodium falciparum k13 C580Y mutants associated with in vitro artemisinin resistance

May 13, 2020 - 14:50 -- Open Access
Author(s): 
Mathieu LC, Cox H, Musset L, et al.
Reference: 
Elife. 2020 May 12;9. pii: e51015

Antimalarial drug resistance has historically arisen through convergent de novo mutations in Plasmodium falciparum parasite populations in Southeast Asia and South America. For the past decade in Southeast Asia, artemisinins, the core component of first-line antimalarial therapies, have experienced delayed parasite clearance associated with several pfk13 mutations, primarily C580Y.

NOT Open Access | P. falciparum artemisinin resistance: the effect of heme, protein damage, and parasite cell stress response

April 27, 2020 - 12:51 -- NOT Open Access
Author(s): 
Rosenthal MR, Ng CL
Reference: 
ACS Infect Dis. 2020 Apr 23

Despite a significant decline in morbidity and mortality over the last two decades, in 2018 there were 228 million reported cases of malaria and 405,000 malaria-related deaths. Artemisinin, the cornerstone of artemisinin-based combination therapies, is the most potent drug in the antimalarial armamentarium against falciparum malaria. Heme-mediated activation of artemisinin and its derivatives results in widespread parasite protein alkylation, which is thought to lead to parasite death.

Insights into the intracellular localization, protein associations and artemisinin resistance properties of Plasmodium falciparum K13

April 21, 2020 - 13:32 -- Open Access
Author(s): 
Gnädig NF, Stokes BH, Fidock DA, et al.
Reference: 
PLoS Pathog 16(4): e1008482

The emergence of artemisinin (ART) resistance in Plasmodium falciparum intra-erythrocytic parasites has led to increasing treatment failure rates with first-line ART-based combination therapies in Southeast Asia. Decreased parasite susceptibility is caused by K13 mutations, which are associated clinically with delayed parasite clearance in patients and in vitro with an enhanced ability of ring-stage parasites to survive brief exposure to the active ART metabolite dihydroartemisinin.

Detection of mutations associated with artemisinin resistance at k13-propeller gene and a near complete return of chloroquine susceptible falciparum malaria in Southeast of Tanzania

March 3, 2020 - 12:39 -- Open Access
Author(s): 
Bwire GM, Ngasala B, Mikomangwa WP, Kilonzi M, Kamuhabwa AAR
Reference: 
Sci Rep. 2020 Feb 26;10(1):3500

In Tanzania, chloroquine was replaced by sulphadoxine- pyrimethamine (SP) as a first-line for treatment of uncomplicated malaria. Due to high resistance in malaria parasites, SP lasted for only 5 years and by the end of 2006 it was replaced with the current artemisinin combination therapy. We therefore, set a study to determine the current genotypic mutations associated with Plasmodium falciparum resistance to artemisinin, partner drugs and chloroquine.

Role of Plasmodium falciparum Kelch 13 Protein Mutations in P. falciparum Populations from Northeastern Myanmar in Mediating Artemisinin Resistance

March 2, 2020 - 15:34 -- Open Access
Author(s): 
Siddiqui FA, Boonhok R, Cui L, et al.
Reference: 
mBio. 2020 Feb 25; 11(1). pii: e01134-19

Mutations in the Plasmodium falciparum Kelch 13 (PfK13) protein are associated with artemisinin resistance. PfK13 is essential for asexual erythrocytic development, but its function is not known. We tagged the PfK13 protein with green fluorescent protein in P. falciparum to study its expression and localization in asexual and sexual stages. We used a new antibody against PfK13 to show that the PfK13 protein is expressed ubiquitously in both asexual erythrocytic stages and gametocytes and is localized in punctate structures, partially overlapping an endoplasmic reticulum marker.

A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites

January 14, 2020 - 16:49 -- Open Access
Author(s): 
Birnbaum J, Scharf S, Schmidt S, Jonscher E, Hoeijmakers WAM, Flemming S, Toenhake CG, Schmitt M, Sabitzki R, Bergmann B, Fröhlke U, Mesén-Ramírez P, Blancke Soares A, Herrmann H, Bártfai R, Spielmann T
Reference: 
Science, 03 Jan 2020: Vol. 367, Issue 6473, pp. 51-59

Artemisinin and its derivatives (ARTs) are the frontline drugs against malaria, but resistance is jeopardizing their effectiveness. ART resistance is mediated by mutations in the parasite’s Kelch13 protein, but Kelch13 function and its role in resistance remain unclear. In this study, we identified proteins located at a Kelch13-defined compartment. Inactivation of eight of these proteins, including Kelch13, rendered parasites resistant to ART, revealing a pathway critical for resistance.

NOT Open Access | Viability Screen of LOPAC1280 Reveals Tyrosine Kinase Inhibitor Tyrphostin A9 as a Novel Partner Drug for Artesunate Combinations To Target the Plasmodium falciparum Ring Stage

April 2, 2019 - 11:46 -- NOT Open Access
Author(s): 
Jie Xin Tong, Sarah E. L. Ang, Esther H. N. Tan and Kevin S. W. Tan
Reference: 
Antimicrob Agents Chemother 63:e02389-18

The emergence of artemisinin-resistant Plasmodium falciparum poses a major threat to current frontline artemisinin combination therapies.

How can interventions that target forest-goers be tailored to accelerate malaria elimination in the Greater Mekong Subregion? A systematic review of the qualitative literature

February 5, 2019 - 16:23 -- Open Access
Author(s): 
Stephanie D. Nofal, Thomas J. Peto, Bipin Adhikari, Rupam Tripura, James Callery, Thanh Mai Bui, Lorenz von Seidlein and Christopher Pell
Reference: 
Malaria Journal 2019 18:32, 1 February 2019

A more detailed characterization of forest activities is needed but research on this topic raises methodological challenges.

A single nucleotide polymorphism in the Plasmodium falciparum atg18 gene associates with artemisinin resistance and confers enhanced parasite survival under nutrient deprivation

October 30, 2018 - 15:46 -- Open Access
Author(s): 
Kimberly F. Breglio, Roberto Amato, Anna Katharina Simon, et al.
Reference: 
Malaria Journal 2018 17:391, 26 October 2018

These results suggest that the atg18 T38I polymorphism may provide additional resistance against artemisinin derivatives, but not partner drugs, even in the absence of kelch13 mutations, and may also be important in parasite survival during nutrient deprivation.

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