K13 propeller

BACKGROUND: Therapeutic efficacy studies (TESs) and detection of molecular markers of drug resistance are recommended by the World Health Organization (WHO) to monitor the efficacy of artemisinin-based combination therapy (ACT). This study assessed the trends of molecular markers of artemisinin resistance and/or reduced susceptibility to lumefantrine using samples collected in TES conducted in Mainland Tanzania from 2016 to 2021. METHODS: A total of 2,015 samples were collected during TES of artemether-lumefantrine at eight sentinel sites (in Kigoma, Mbeya, Morogoro, Mtwara, Mwanza, Pwani, Tabora, and Tanga regions) between 2016 and 2021...

CONTEXT: Resistance to antimalarial drugs is one of the major challenges for malaria elimination. In India, artemisinin combination therapy (artesunate-sulfadoxin pyrimethamine) was introduced in place of chloroquine (CQ) for the treatment of uncomplicated falciparum malaria in 2010. Periodical monitoring of polymorphisms in antimalarial drug resistance marker genes will be useful for assessing drug pressure, mapping and monitoring of drug resistance status; and will be helpful for searching alternative treatments...

RNF168 plays a central role in the DNA damage response (DDR) by ubiquitylating histone H2A at K13 and K15. These modifications direct BRCA1-BARD1 and 53BP1 foci formation in chromatin, essential for cell-cycle-dependent DNA double-strand break (DSB) repair pathway selection. The mechanism by which RNF168 catalyzes the targeted accumulation of H2A ubiquitin conjugates to form repair foci around DSBs remains unclear. Here, using cryoelectron microscopy (cryo-EM), nuclear magnetic resonance (NMR) spectroscopy, and functional assays, we provide a molecular description of the reaction cycle and dynamics of RNF168 as it modifies the nucleosome and recognizes its ubiquitylation products...

BACKGROUND: Emerging artemisinin resistance and diagnostic resistance are a threat to malaria control in Africa. Plasmodium falciparum kelch13 (K13) propeller-domain mutations that confer artemisinin partial resistance have emerged in Africa. K13-561H was initially described at a frequency of 7.4% from Masaka in 2014-2015 but not present in nearby Rukara. By 2018, 19.6% of isolates in Masaka and 22% of isolates in Rukara contained the mutation. Longitudinal monitoring is essential to inform control efforts...

Malaria is a significant global health concern, with a majority of cases in Sub-Saharan African nations. Numerous antimalarial drugs have been developed to counter the rampant prevalence of Plasmodium falciparum malaria. Artemisinin-based Combination Therapy (ACT) has served as the primary treatment of uncomplicated malaria in Ghana since 2005. However, a growing concern has emerged due to the escalating reports of ACT resistance, particularly in Southeast Asia, and its encroachment into Africa. Specifically, mutations in the Kelch propeller domain on chromosome 13 (Pfk13) have been linked to ACT resistance...

Artemisinin-combined treatments are the recommended first-line treatment of Plasmodium falciparum malaria, but they are being threatened by emerging artemisinin resistance. Mutations in pfk13 are the principal molecular marker for artemisinin resistance. This study characterizes the presence of mutations in pfk13 in P. falciparum in Western Equatoria State, South Sudan. We analyzed 468 samples from patients with symptomatic malaria and found 15 mutations (8 nonsynonymous and 7 synonymous). Each mutation appeared only once, and none were validated or candidate markers of artemisinin resistance...

Malaria still poses a major burden on human health around the world, especially in endemic areas. Plasmodium resistance to several antimalarial drugs has been one of the major hindrances in control of malaria. Thus, the World Health Organization recommended artemisinin-based combination therapy (ACT) as a front-line treatment for malaria. The emergence of parasites resistant to artemisinin, along with resistant to ACT partner drugs, has led to ACT treatment failure. The artemisinin resistance is mostly related to the mutations in the propeller domain of the kelch13 (k13) gene that encodes protein Kelch13 (K13)...

BACKGROUND: Malaria remains one of the most serious public health problems in sub-Saharan Africa and Mozambique is the world's fourth largest contributor, with 4.7% of disease cases and 3.6% of total deaths due to malaria. Its control relies on the fight against the vector and treatment of confirmed cases with anti-malarial drugs. Molecular surveillance is an important tool for monitoring the spread of anti-malarial drug resistance. METHODS: A cross-sectional study recruited 450 participants with malaria infection detected by Rapid Diagnostic Tests, from three different study sites (Niassa, Manica and Maputo) between April and August 2021...

BACKGROUND: The spread of artemisinin (ART)-resistant Plasmodium falciparum threatens the control of malaria. Mutations in the propeller domains of P. falciparum Kelch13 ( k13 ) are strongly associated with ART resistance. Ferredoxin (Fd), a component of the ferredoxin/NADP+ reductase (Fd/FNR) redox system, is essential for isoprenoid precursor synthesis in the plasmodial apicoplast, which is important for K13-dependent hemoglobin trafficking and ART activation. Therefore, Fd is an antimalarial drug target and fd mutations may modulate ART sensitivity...

BACKGROUND: Currently, chemotherapy stands out as the major malaria intervention strategy, however, anti-malarial resistance may hamper global elimination programs. Artemisinin-based combination therapy (ACT) stands as the drug of choice for the treatment of Plasmodium falciparum malaria. Plasmodium falciparum kelch13 gene mutations are associated with artemisinin resistance. Thus, this study was aimed at evaluating the circulation of P. falciparum k13 gene polymorphisms from Kisii County, Kenya during an era of ACT deployment...

Artemisinin combination therapies (ACTs) have led to a significant decrease in Plasmodium falciparum malaria mortality. This progress is now threatened by emerging artemisinin resistance (ART-R) linked originally in SE Asia to polymorphisms in the Kelch propeller protein (K13) and more recently to several other seemingly unrelated genetic mutations. To better understand the parasite response to ART, we are characterizing a P. falciparum mutant with altered sensitivity to ART that was created via piggyBac transposon mutagenesis...

Introduction: Artemisinin-based combination therapies (ACTs) act as first-line antimalarial drugs and play a crucial role in the successful control of falciparum malaria. However, the recent emergence of resistance of Plasmodium falciparum to ACTs in South East Asia is of particular concern. Hence, there is an urgent need to identify the genetic determinants of and understand the molecular mechanisms underpinning such resistance. Artemisinin resistance (AR) is primarily driven by the mutations in the P...

P. falciparum Kelch 13 (Pfk13) is an essential protein that contains BTB and Kelch-repeat propeller domains (KRPD), which was predicted to bind substrate during ubiquitin-dependent degradation pathway. However, the function of Pfk13 and the structural alterations associated with artemisinin resistance mutations remain unknown. Herein, we screened two proteins, namely Pfk13-F446I and Pfk13-C580Y, which are closely associated with artemisinin, for structural prediction analysis. The 389 amino acids from 1011 nt to 2178 nt of KRPD were cloned into pFastBacTM 1...

Plasmodium falciparum infects millions and kills thousands of people annually the world over. With the emergence of artemisinin and/or multidrug resistant strains of the pathogen, it has become even more challenging to control and eliminate the disease. Multiomics studies of the parasite have started to provide a glimpse into the confounding genetics and mechanisms of artemisinin resistance and identified mutations in Kelch13 (K13) as a molecular marker of resistance. Over the years, thousands of genomes and transcriptomes of artemisinin-resistant/sensitive isolates have been documented, supplementing the search for new genes/pathways to target artemisinin-resistant isolates...

BACKGROUND: The fast-declining clinical efficacy of dihydroartemisinin-piperaquine (DHA-PPQ) in Cambodia is a warning of the underlying westward dissemination of piperaquine resistance in the Greater Mekong Subregion (GMS). Mutations in the Plasmodium falciparum Kelch 13-propeller (PfK13) and the P. falciparum chloroquine resistance transporter (PfCRT), as well as plasmepsin 2/3 gene amplification, have been discovered as molecular markers for predicting DHA-PPQ treatment failure. Determining whether these genetic variations of P...

Introduction: Drug resistance remains a major challenge in malaria treatment, especially after the emergence of resistance to artemisinin-based combined therapies. Plasmodium falciparum Kelch13 gene mutations are implicated in conferring artemisinin resistance. Thus, this study was aimed at determining the occurrence of Kelch13 ( K13 ) propeller resistance gene polymorphism mutations in Bushenyi district, Uganda. Methods: Participants suspected to have malaria were recruited...

BACKGROUND: The occurrence of artemisinin resistance (ART)-associated polymorphism of Plasmodium falciparum K13-propeller (pfk13) gene before and after the introduction of artemisinin-based combination therapy (ACT) in two regions of Nigeria was investigated in this study. Regular surveillance is necessary to make a definite conclusion on the emergence and pattern of possible resistance to ART. METHODS: This cross-sectional study was carried out in the Southwestern and Southeastern geopolitical zones of Nigeria...

Partial artemisinin resistance, defined in patients as a delayed parasite clearance following artemisinin-based treatment, is conferred by non-synonymous mutations in the Kelch beta-propeller domain of the Plasmodium falciparum k13 ( pfk13 ) gene. Here, we carried out in vitro selection over a 1-year period on a West African P. falciparum strain isolated from Kolle (Mali) under a dose-escalating artemisinin regimen. After 18 cycles of sequential drug pressure, the selected parasites exhibited enhanced survival to dihydroartemisinin in the ring-stage survival assay (RSA0-3h = 9...

BACKGROUND: Artemisinin-based treatment in malaria patients with abnormal hemoglobin may be ineffective because of their genetic particularity, which could lead to resistance. The main purpose of this study was to assess the effect of artemisinin derivatives on in vivo parasite clearance according to erythrocyte variants. In vivo response was investigated through retrospective data obtained over a 42-day artemether-lumefantrine/artesunate amodiaquine efficacy protocol conducted from 2012 to 2016...

The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failure across Southeast Asia. In Africa, K13- propeller genotyping confirms the emergence of the R561H mutation in Rwanda and highlights the continuing dominance of wild-type K13 elsewhere. Using gene editing, we show that R561H, along with C580Y and M579I, confer elevated in vitro ART resistance in some African strains, contrasting with minimal changes in ART susceptibility in others...