A novel intron variant is associated with emerging pfdhps mutant haplotypes in West and Central African Plasmodium falciparum.

Sulfadoxine-pyrimethamine plays a key role in Plasmodium falciparum chemoprevention across Africa, yet the protective efficacy of SP is undermined by mutations conferring resistance in the genes encoding dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps). The emergence and spread of the pfdhps 431V mutation suggests that this may confer resistance and be selected by drug use. Here, we report a non-coding mutation a548383t, which expands a di-nucleotide repeat in the first intron of pfpppk-dhps.

Optimization and Characterization of the Antimalarial Activity of -Aryl Acetamides that are Susceptible to Mutations in ROM8 and CSC1.

New antimalarials are needed due to the threat of emerging resistance against existing antimalarial therapies. A phenotypic screen uncovered the -aryl acetamide class that inhibits the development of asexual ring-stage parasites. The structure-activity relationship of this class was investigated, and key modifications were introduced that produced WEHI-326 with potent antimalarial activity.

A case of malaria presenting 13 years after leaving an endemic area.

usually causes an acute malaria infection, with symptoms presenting from 8 to 11 days onwards following inoculation by an infected mosquito. However, evidence suggesting chronic carriage of blood-stage infection, which can lead to recrudescence of parasitaemia as immunity wanes, has been documented in migrants from malaria-endemic to non-endemic regions. We report the case of a pregnant patient who presented in late 2020 with symptomatic malaria, having lived continuously in areas non-endemic for malaria (Spain and the UK) for 13 years.

Impact of dhps mutations on sulfadoxine-pyrimethamine protective efficacy and implications for malaria chemoprevention.

Sulfadoxine-pyrimethamine (SP) is recommended for perennial malaria chemoprevention in young children in high burden areas across Africa. Mutations in the dihydropteroate synthase (dhps) gene (437 G/540E/581 G) associated with sulfadoxine resistance vary regionally, but their effect on SP protective efficacy is unclear. We retrospectively analyse time to microscopy and PCR-confirmed re-infection in seven efficacy trials including 1639 participants in 12 sites across Africa.

Optimization and Characterization of N-Acetamide Indoles as Antimalarials That Target PfATP4.

To discover new antimalarials, a screen of the Janssen Jumpstarter library against uncovered the N-acetamide indole hit class. The structure-activity relationship of this chemotype was defined and culminated in the optimized frontrunner analog WJM664, which exhibited potent asexual stage activity and high metabolic stability. Resistant selection and whole-genome sequencing revealed mutations in PfATP4, which was validated as the target by showing that analogs exhibited reduced potency against parasites with resistance-conferring mutations in PfATP4, a metabolomic signature similar to that of the PfATP4 inhibitor KAE609, and inhibition of Na-dependent ATPase activity consistent with on-target inhibition of PfATP4.

Improved limit of detection for zoonotic Plasmodium knowlesi and P. cynomolgi surveillance using reverse transcription for total nucleic acid preserved samples or dried blood spots.

Background: Zoonotic P. knowlesi and P. cynomolgi symptomatic and asymptomatic infections occur across endemic areas of Southeast Asia.

Drug resistance-associated mutations in Plasmodium UBP-1 disrupt its essential deubiquitinating activity.

Deubiquitinating enzymes function to cleave ubiquitin (Ub) moieties from modified proteins, serving to maintain the pool of free Ub in the cell while simultaneously impacting the fate and function of a target protein. Like all eukaryotes, Plasmodium parasites rely on the dynamic addition and removal of Ub for their own growth and survival. While humans possess around 100 deubiquitinases, Plasmodium contains ∼20 putative Ub hydrolases, many of which bear little to no resemblance to those of other organisms.

Blood Transfusions for Chronic Malaria Anemia in Prisoners of War on the Thai-Burma Railway 1943-1945.

Allied prisoners of war (POWs) working on the Imperial Japanese Army's railroad from Thailand to Burma during 1943-1945 devised a blood transfusion service to rescue severely ill fellow prisoners who were otherwise unlikely to survive the war. Extant transfusion records (1,251 recipients, 1,189 donors) in ledger books held by the United Kingdom National Archives at Kew were accessed and analyzed. Survival to the end of the war in 1945 was determined from Commonwealth War Graves Commission records.

Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility.

Plasmodium malariae parasites are widely observed across the tropics and sub-tropics. This slow-growing species, known to maintain chronic asymptomatic infections, has been associated with reduced antimalarial susceptibility. We analyse 251 P.

Genomic analysis of global Plasmodium vivax populations reveals insights into the evolution of drug resistance.

Increasing reports of chloroquine resistance (CQR) in Plasmodium vivax endemic regions have led to several countries, including Indonesia, to adopt dihydroarteminsin-piperaquine instead. However, the molecular drivers of CQR remain unclear. Using a genome-wide approach, we perform a genomic analysis of 1534 P.

Asymptomatic Plasmodium falciparum infections and determinants of carriage in a seasonal malaria chemoprevention setting in Northern Cameroon and south Senegal (Kedougou).

Background: Among the several strategies recommended for the fight against malaria, seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine combination (SPAQ) targets children 3 months to 5 years in Sahel regions of Africa to reduce mortality and mortality. Since SMC with SPAQ is administered to symptoms-free children for prevention of malaria, it is anticipated that a proportion of asymptomatic parasitaemic children will also be treated and may result in a drop in both the overall population prevalence of asymptomatic malaria infections, subsequent risk of symptomatic malaria infections and transmission. Age-specific carriage of asymptomatic Plasmodium spp.

The spread of molecular markers of artemisinin partial resistance and diagnostic evasion in Eritrea: a retrospective molecular epidemiology study.

Background: Eritrea was the first African country to discontinue the use of histidine rich protein 2 (HRP2)-detecting rapid diagnostic tests (RDTs) for malaria diagnosis following reports of a high prevalence of pfhrp2/3-deleted Plasmodium falciparum parasites causing false-negative results in the country. Eritrea was also the first African country to report partial artemisinin resistance due to the P falciparum kelch13 (pfk13) Arg622Ile mutation. We aimed to characterise the spatial distribution of pfk13 mutants and their interactions with pfhrp2/3 deletions in Eritrea and to assess the role of the use of HRP2-detecting RDTs and antimalarial (artesunate-amodiaquine) therapy in the spread of the two variants.

Parasite clearance and protection from Plasmodium falciparum infection (PCPI): a three-arm, parallel, double-blinded, placebo-controlled, randomised trial of presumptive sulfadoxine-pyrimethamine versus sulfadoxine-pyrimethamine plus amodiaquine versus artesunate monotherapy among asymptomatic children 3-5 years of age in Cameroon.

Background: The World Health Organization 2022 malaria chemoprevention guidelines recommend providing a full course of antimalarial treatment at pre-defined intervals, regardless of malaria status to prevent illness among children resident in moderate to high perennial malaria transmission settings as perennial malaria chemoprevention (PMC) with sulfadoxine-pyrimethamine (SP). The dhps I431V mutation circulating in West Africa has unknown effect on SP protective efficacy.

Methods: This protocol is for a three-arm, parallel, double-blinded, placebo-controlled, randomised trial in Cameroon among children randomly assigned to one of three directly-observed treatment groups: (i) Group 1 (n = 450) receives daily artesunate (AS) placebo on days - 7 to -1, then active SP plus placebo amodiaquine (AQ) on day 0, and placebo AQ on days 1 and 2; (ii) Group 2 (n = 250) receives placebo AS on days - 7 to -1, then active SP and AQ on day 0, and active AQ on days 1 and 2; and (iii) Group 3 (n = 200) receives active AS on days - 7 to -1, then placebo SP on day 0 and placebo AQ on days 0 to 2.

A Pan Plasmodium lateral flow recombinase polymerase amplification assay for monitoring malaria parasites in vectors and human populations.

Robust diagnostic tools and surveillance are crucial for malaria control and elimination efforts. Malaria caused by neglected Plasmodium parasites is often underestimated due to the lack of rapid diagnostic tools that can accurately detect these species. While nucleic-acid amplification technologies stand out as the most sensitive methods for detecting and confirming Plasmodium species, their implementation in resource-constrained settings poses significant challenges.

Property and Activity Refinement of Dihydroquinazolinone-3-carboxamides as Orally Efficacious Antimalarials that Target PfATP4.

To contribute to the global effort to develop new antimalarial therapies, we previously disclosed initial findings on the optimization of the dihydroquinazolinone-3-carboxamide class that targets PfATP4. Here we report on refining the aqueous solubility and metabolic stability to improve the pharmacokinetic profile and consequently in vivo efficacy. We show that the incorporation of heterocycle systems in the 8-position of the scaffold was found to provide the greatest attainable balance between parasite activity, aqueous solubility, and metabolic stability.

Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1.

With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1).

Measuring protective efficacy and quantifying the impact of drug resistance: A novel malaria chemoprevention trial design and methodology.

Background: Recently revised WHO guidelines on malaria chemoprevention have opened the door to more tailored implementation. Countries face choices on whether to replace old drugs, target additional age groups, and adapt delivery schedules according to local drug resistance levels and malaria transmission patterns. Regular routine assessment of protective efficacy of chemoprevention is key.

Improved limit of detection for zoonotic and surveillance using reverse transcription for total nucleic acid preserved samples or dried blood spots.

Background: Zoonotic and symptomatic and asymptomatic infections occur across endemic areas of Southeast Asia. Most infections are low-parasitemia, with an unknown proportion below routine microscopy detection thresholds. Molecular surveillance tools optimizing the limit of detection (LOD) would allow more accurate estimates of zoonotic malaria prevalence.

New reference genomes to distinguish the sympatric malaria parasites, Plasmodium ovale curtisi and Plasmodium ovale wallikeri.

Despite Plasmodium ovale curtisi (Poc) and wallikeri (Pow) being important human-infecting malaria parasites that are widespread across Africa and Asia, little is known about their genome diversity. Morphologically identical, Poc and Pow are indistinguishable and commonly misidentified. Recent rises in the incidence of Poc/Pow infections have renewed efforts to address fundamental knowledge gaps in their biology, and to develop diagnostic tools to understand their epidemiological dynamics and malaria burden.