Artemisinin-based Combination Therapy Research Articles

Evaluation of In Vitro Inhibition of β-Hematin Formation: A Step Towards a Comprehensive Understanding of the Mechanism of Action of New Arylamino Alcohols

Currently, artemisinin-based combination therapy is recommended as first-line treatment of uncomplicated falciparum malaria. Arylamino alcohols (AAAs) such as mefloquine (MQ) are the preferred partner drugs due to their longer half-life, reliable absorption and strong antimalarial activity. However, the mode of action of MQ remains poorly understood and its neurotoxicity limits its use. Furthermore, the emergence of drug-resistant parasites requires development of new antimalarial drugs. The aim of this study was to evaluate the β-hematin inhibition capacity of three pairs of enantiopure AAAs 1–3 (a/S and b/R) derived from MQ or enpiroline (ENP), a pyridine-based MQ analog with strong antimalarial activity. Inhibition of β-hematin—the synthetic counterpart of hemozoin formation—was determined for each compound. Antimalarial activity against W2 and 3D7 Plasmodium falciparum strains as well as percentages of inhibition of β-hematin formation were compared to those of reference molecules, i.e., chloroquine (CQ), MQ and ENP. Furthermore, a cytotoxicity study on the human-derived hepatocarcinoma cell line HepG2 was performed. With high antimalarial activity, stronger ability to inhibit β-hematin formation and low cytotoxicity, AAAs 1a-b and 2a are the most promising. These findings provide a better understanding of their potential mechanisms of action and may pave the way toward developing new lead compounds.

Accelerating Antimalarial Drug Discovery with a New High-Throughput Screen for Fast-Killing Compounds.

The urgent need for rapidly acting compounds in the development of antimalarial drugs underscores the significance of such compounds in overcoming resistance issues and improving patient adherence to antimalarial treatments. The present study introduces a high-throughput screening (HTS) approach using 1536-well plates, employing Plasmodium falciparum lactate dehydrogenase (PfLDH) combined with nitroreductase (NTR) and fluorescent probes to evaluate inhibition of the growth of the asexual blood stage of malaria parasites. This method was adapted to efficiently assess the speed of action profiling (SAP) in a 384-well plate format, streamlining the traditionally time-consuming screening process. By successfully screening numerous compounds, this approach identified fast-killing hits early in the screening process, addressing challenges associated with artemisinin-based combination therapies. The high-throughput SAP method is expected to be of value in continuously monitoring fast-killing properties during structure-activity relationship studies, expediting the identification and development of novel, rapidly acting antimalarial drugs within phenotypic drug discovery campaigns.

Polymorphisms in the Pfcrt, Pfmdr1, and Pfk13 genes of Plasmodium falciparum isolates from southern Brazzaville, Republic of Congo

This study aimed to analyze polymorphisms in Pfcrt, Pfmdr1, and Pfk13 genes’ markers of resistance to Artemisinin-based combination therapy (ACT), in Plasmodium falciparum isolates from southern Brazzaville, 15 years after the adoption of ACT in the Republic of Congo. A total of 369 microscopy-confirmed malaria-infected individuals were enrolled from March to October 2021 in the community and in health facilities during a cross-sectional study. The K76T mutation in the Pfcrt gene, N86Y and Y184F mutations in the Pfmdr1 gene were investigated using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) while the codons region (1005–1300) of the Pfmdr1gene, and Pfk13 gene were sequenced. The prevalences of K76T, N86Y, Y184F mutations were 26.0%, 6.8%, and 27.7%, respectively. However, no mutations were detected in codons 1034, 1042, and 1246 of the Pfmdr1 gene. None of the mutations previously associated with artemisinin-based resistance were detected in the Pfk13 gene. The results reveal a significant decrease in the prevalence of K76T, N86Y, Y184F mutations, in Plasmodium falciparum isolates following the change of therapeutic policy. As artemisinin resistance is emerging throughout Africa, continued surveillance for early detection of these mutations and relevant partner markers of drug resistance are recommended in the Republic of Congo.

Dihydroartemisinin-Piperaquine Combination in the Treatment of Uncomplicated Plasmodium falciparum Malaria: Update on Clinical Failures in Africa and Tools for Surveillance.

Dihydroartemisinin (or artenimol)-piperaquine is one of the six artemisinin-based combination therapies recommended in uncomplicated malaria treatment. However, artemisinin partial resistance has been reported in Cambodia, Laos, Vietnam, India, and, recently, in Africa. Polymorphisms in the Pfk13 gene have been described as molecular markers of artemisinin resistance and the amplification of the plasmepsine II/III (Pfpmp2/Pfpmp3) gene has been associated with piperaquine resistance. However, some therapeutic failures with this combination remain unexplained by strains' characterization. We provide an overview on the use of dihydroartemisinin-piperaquine in malaria treatment and discuss tools available to monitor its efficacy.

Exploring the Antimalarial Efficacy of Globimetula oreophila Leaf Fractions in Plasmodium berghei-Infected Mice: In Vivo Approach

The development of parasite resistance to first-line antimalarial medicines, especially the Artemisinin-based combination therapies (ACTs), has made the research and development of novel antimalarial medications vital. Globimetula oreophila, a plant used in traditional medicine to treat malaria, is a natural product that may provide new antimalarial drugs with fewer side effects, greater efficacy and lower risk of resistance than synthetic drugs. This study aims to evaluate the antiplasmodial properties of G. oreophila's fractions. The plant leaves were air-dried and reduced in size using a pestle and mortar. The pulverized plant was macerated in 70% ethanol and fractionated with solvent in increasing polarity of n-hexane, chloroform, ethyl acetate, and n-butanol to produce the various fractions. The antiplasmodial activity of the n-hexane, chloroform, ethyl acetate, and n-butanol fractions of G. oreophila leaf extract was assessed using an in vivo method in Plasmodium berghei-infected mice via prophylactic, suppressive, and curative test. The fractions' median lethal dose (LD50) was estimated to be greater than 5000 mg/kg in mice. The median effective dose (ED50) of the fractions at doses of 125, 250, and 500 mg/kg produced a significant (p<0.001) decrease in the level of parasitemia. The ethyl acetate fraction had the best antiplasmodium activity compared to other plant fractions. The fractions of G. oreophila showed significant in vivo antiplasmodial activity, which upholds the earlier in vivo findings for the crude extract and its folkloric use. Further study should be carried out to isolate active secondary metabolites responsible for this observed antimalarial activity in all four investigated fractions.

Impact of Climate Variability and Interventions on Malaria Incidence and Forecasting in Burkina Faso.

Malaria remains a climate-driven public health issue in Burkina Faso, yet the interactions between climatic factors and malaria interventions across different zones are not well understood. This study estimates time delays in the effects of climatic factors on malaria incidence, develops forecasting models, and assesses their short-term forecasting performance across three distinct climatic zones: the Sahelian zone (hot/arid), the Sudano-Sahelian zone (moderate temperatures/rainfall); and the Sudanian zone (cooler/wet). Monthly confirmed malaria cases of children under five during the period 2015-2021 were analyzed using Bayesian generalized autoregressive moving average negative binomial models. The predictors included land surface temperature (LST), rainfall, the coverage of insecticide-treated net (ITN) use, and the coverage of artemisinin-based combination therapies (ACTs). Bayesian variable selection was used to identify the time delays between climatic suitability and malaria incidence. Wavelet analysis was conducted to understand better how fluctuations in climatic factors across different time scales and climatic zones affect malaria transmission dynamics. Malaria incidence averaged 9.92 cases per 1000 persons per month from 2015 to 2021, with peak incidences in July and October in the cooler/wet zone and October in the other zones. Periodicities at 6-month and 12-month intervals were identified in malaria incidence and LST and at 12 months for rainfall from 2015 to 2021 in all climatic zones. Varying lag times in the effects of climatic factors were identified across the zones. The highest predictive power was observed at lead times of 3 months in the cooler/wet zone, followed by 2 months in the hot/arid and moderate zones. Forecasting accuracy, measured by the mean absolute percentage error (MAPE), varied across the zones: 28% in the cooler/wet zone, 53% in the moderate zone, and 45% in the hot/arid zone. ITNs were not statistically important in the hot/arid zone, while ACTs were not in the cooler/wet and moderate zones. The interaction between climatic factors and interventions varied across zones, with the best forecasting performance in the cooler/wet zone. Zone-specific intervention planning and model development adjustments are essential for more efficient early-warning systems.

Evaluating the Genetic Landscape of (Plasmodium falciparum) PfKelch13 Gene Polymorphisms in Côte d'Ivoire Following a Decade of Artemisinin-based Combination Therapy

Introduction: Artemisinin-based combination therapies (ACTs) are the mainstay of malaria treatment globally. However, their effectiveness is threatened by the emergence of resistance in Plasmodium falciparum (P.f), particularly in Southeast Asia (SEA). Specific mutations within the pfKelch13 gene, such as Cys-580-Tyr, Arg-539-Thr, Tyr-493-His, and Ile-543-Thr, have been strongly linked to delayed parasite clearance following ACT treatment. This study aimed to investigate polymorphisms within the pfKelch13 gene (also known as the K13-propeller or K13 gene) in four regions of Côte d'Ivoire. Côte d'Ivoire experiences year-round malaria transmission and has utilized ACTs for over a decade. Methods: From September 2013 to July 2014, samples were collected from patients residing in Abidjan (south), Ayamé (southeast), Man (west), and Korhogo (north) who presented with microscopically confirmed uncomplicated malaria. Following Plasmodium falciparum DNA extraction, nested PCR was employed to amplify an 849 bp fragment of the pfKelch13 gene. Amplicons were subsequently sequenced and analyzed using BioEdit software. Results: 531 DNA sequences were analyzed including 301 (58.7%) from Abidjan, 61(11.5%) from Ayamé, 93 (17.5%) from Man and 76 (13.4%) from Korhogo. Only 20 isolates carrying 22 mutations were observed including 6 non-synonymous single-nucleotide polymorphisms (nsSNP): 4 in Abidjan (Asp-535-Met; Ala-578-Ser; Phe-583-Ser and Ile-601-Thr) and 2 in Korhogo (Asp-559-Asn and Val-510-Met). Only synonymous SNP (sSNP) were identified in the two other Towns. The proportion of mutated pfK13 sequences is 3.8% (20/531). Conclusion: The identification of non-synonymous mutations in this study underscores the importance of heightened surveillance for potential ACT resistance in Plasmodium falciparum within Côte d'Ivoire. Combining in vitro assays, such as the Ring-stage Survival Assay, with molecular testing will be crucial for definitively determining the phenotypic impact of these mutations on parasite susceptibility to ACTs.

Recent Advances in the Treatment of Malaria.

Malaria is still one of the major global health challenges affecting millions annually, particularly in non-Mediterranean Africa and Southeast Asia. Over the past two decades, substantial progress has been made in reducing malaria-related morbidity and mortality, primarily due to advancements in antimalarial therapeutics. This review provides a comprehensive overview of recent developments in malaria treatment, focusing on the evolution of drug therapies, mechanisms of action, and emerging resistance patterns. The cornerstone of current treatment strategies is artemisinin-based combination therapies (ACTs), which have proven highly effective against P. falciparum and P. vivax, the most prevalent malaria-causing parasites. However, the onset of artemisinin resistance, particularly in Southeast Asian countries, poses a significant threat to these gains. Additionally, other antimalarial classes, including quinine derivatives, 8-aminoquinolines, and antifolate drugs, are examined for their efficacy, resistance mechanisms, and future potential. This review also discusses the challenges associated with drug resistance, the genetic underpinnings of resistance in malaria parasites, and the implications for future treatment protocols. Furthermore, the review examines combinational therapies, such as triple artemisinin combination therapies (TACTs), and vaccines that are approved or in development to circumvent resistance issues. The need for continuous surveillance, innovative therapeutic strategies, and advances in novel antimalarial therapeutic agents is emphasized to sustain and further progress in the control of malaria and its eventual eradication.

Triple artemisinin-based combination therapy (TACT): Efficacy of dihydroartemisinin-piperaquine plus chloroquine against Plasmodium berghei ANKA strains with different drug sensitivities in a murine malaria model

BackgroundEvident detection of artemisinin resistance markers in patient isolates of Plasmodium falciparum from East Africa threatens the efficacy of artemisinin-based combination therapies (ACTs) as first-line treatment of malaria in sub-Saharan Africa. Repositioning previously used antimalarials as complementary addition to ACTs has been suggested as a viable option to mitigating this threat. This study evaluated the potential benefit of chloroquine (CQ) as a complementary partner to dihydroartemisinin/piperaquine (DHA/PQ) in the treatment of malaria in a mice model. MethodsThe comparative efficacy of the combination of DHA/PQ/CQ and DHA/PQ against two strains of Plasmodium berghei ANKA (MRA 311 and 671) with different levels of sensitivities to chloroquine was evaluated in separate experiments. Parasitological activities including; parasite suppression time, parasite clearance time, recrudescence time, and parasite reduction ratio were evaluated in vivo. The mean survival time was also monitored throughout the duration of the study. ResultsIn both parasite lines, 99.99 % chemo-suppression was observed on day 4 in the drug treatment groups (CQ alone, DHA/PQ and DHA/PQ/CQ). In the curative test, there were significant differences between DHA/PQ/CQ and DHQ/PQ treatment, highlighted by reduced parasite clearance time (4.75 ± 0.3 Vs 5.5 ± 0.3 days, P < 0.05), significantly delayed recrudescence time (28.5 ± 1.04 Vs 13.3 ± 0.48 days, P < 0.01), a 1.5-fold change in parasite reduction ratio, and a prolonged mean survival time (34.5 ± 1.04 Vs 26.7 ± 0.48 days, P < 0.05). ConclusionThe addition of chloroquine to dihydroartemisinin-piperaquine may be beneficial in the treatment of malaria, especially in areas where malaria parasite sensitivity to chloroquine is predominant.

A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants

Artemisinin-based combination therapy (ACT) is the mainstay of effective treatment of Plasmodium falciparum malaria. However, the long-term utility of ACTs is imperiled by widespread partial artemisinin resistance in Southeast Asia and its recent emergence in parts of East Africa. This underscores the need to identify chemotypes with new modes of action (MoAs) to circumvent resistance to ACTs. In this study, we characterized the asexual blood stage antiplasmodial activity and resistance mechanisms of LDT-623, a 4-aminoquinoline (4-AQ). We also detected LDT-623 activity against multiple stages (liver schizonts, stage IV-V gametocytes, and ookinetes) of Plasmodium’s life cycle, a feature unlike other 4-AQs such as chloroquine (CQ) and piperaquine (PPQ). Using heme fractionation profiling and drug uptake studies in PfCRT-containing proteoliposomes, we observed inhibition of hemozoin formation and PfCRT-mediated transport, which constitute characteristic features of 4-AQs’ MoA. We also found minimal cross-resistance to LDT-623 in a panel of mutant pfcrt or pfmdr1 lines, but not the PfCRT F145I mutant that is highly resistant to PPQ resistance yet is very unfit. No P. falciparum parasites were recovered in an in vitro resistance selection study, suggesting a high barrier for resistance to emerge. Finally, a competitive growth assay comprising &gt;50 barcoded parasite lines with mutated resistance mediators or major drug targets found no evidence of cross-resistance. Our findings support further exploration of this promising 4-AQ.

The Antiviral and Antimalarial Prodrug Artemisinin from the Artemisia Species: A Review.

Artemisinin is a truly fascinating drug in many ways. Since the unrestrained procedure of its detection, as an antimalarial drug, artemisinin has received a great deal of consideration. Recently, application of artemisinin-based combination therapy has been broadly applied for treating numerous ailments. Moreover, as an antimalarial compound, artemisinin and its associated compounds have abundant healing efficacy and can be repurposed for additional symptoms, like autoimmune infections, cancer, and viral contaminations. Recently a number of studies have highlighted the significance of the artemisinin-related compounds in SARS-CoV-2 treatment. The current review purposes to present a concise account of the history of the antiviral and antimalarial prodrugs-Artemisinin, from the Artemisia species. It is followed by its antiviral, antimalarial prospective, chemical nature and extraction procedure, photochemistry, mechanism of action, and its clinical trials and patents, and accentuates the significance of the mechanistic studies concerned for therapeutic results, both in viral and malarial circumstances.

Presence of Plasmodium falciparum strains with artemisinin-resistant K13 mutation C469Y in Busia County, Western Kenya

Malaria remains a key health and economic problem, particularly in sub-Saharan Africa. The emergence of artemisinin drug resistance (ART-R) parasite strains poses a serious threat to the control and elimination of this scourge. This is because artemisinin-based combination therapies (ACTs) remain the first-line treatment in the majority of malaria-endemic regions in Sub-Saharan Africa. Certain single-nucleotide polymorphisms in the propeller domains of Plasmodium falciparum Kelch 13 protein (K13) have been associated with delayed parasite clearance in vivo and in vitro. These mutations serve as vital molecular markers for tracking the emergence and dispersion of resistance. Recently, there have been increasing reports of the emergence and spread of P. falciparum ART-R parasites in the Eastern Africa region. This necessitates continued surveillance to best inform mitigation efforts. This study investigated the presence of all reported mutations of K13 propeller domains in the parasite population in Busia County, Kenya, a known malaria-endemic region. Two hundred twenty-six participants with microscopically confirmed uncomplicated malaria were recruited for this study. They were treated with artemether–lumefantrine under observation for the first dose, and microscopic examination was repeated 1 day later after ensuring the participants had taken the second and third doses. P. falciparum DNA from all samples underwent targeted amplification of the K13 gene using a semi-nested PCR approach, followed by Sanger sequencing. The recently validated ART-R K13 mutation C469Y was identified in three samples. These three samples were among 63 samples with a low reduction in parasitemia on day 1, suggesting day 1 parasitemia reduction rate is a useful parameter to enrich the ART-R parasites for further analysis. Our findings highlight the need for continuous surveillance of ART-R in western Kenya and the region to determine the spread of ART-R and inform containment.

Intermittent Preventive Treatment of Malaria in Pregnancy and the Impact on Neonates in African Countries as Assessed by Entropy Weight and TOPSIS Methods.

Background/Objectives: In regions of Africa with a high prevalence of malaria, pregnant women in their first or second trimester should be administered intermittent preventive treatment in pregnancy (IPTp). However, infants may contract malaria despite the IPTp therapy that their mothers have received. The objective of the present investigation was to assess the symptoms and various treatments for neonatal malaria. Methods: Entropy weight and TOPSIS were used to achieve the study goal. The TOPSIS multi-attribute decision-making system was used to assess newborn malaria symptoms and select the optimal treatment, even for mothers receiving IPTp medication during pregnancy. The entropy weight approach calculated TOPSIS attribute weights. The present research used UNICEF data for 14 African nations in 2023. Results: The results indicated that neonates whose mothers received IPTp therapy ultimately contracted malaria, with diarrhea being the primary symptom. It is important to note that health providers administer a combination of zinc and oral rehydration solution (ORS) to infants as the most effective treatment for malaria symptoms, thereby abandoning the first-line treatment for malaria, artemisinin-based combination therapy (ACT). Conclusions: The most effective treatment for neonatal malaria is a combination of zinc and ORS, although less than half of children in Africa have access to ORS. Therefore, the findings of this study may encourage African countries to prioritize co-pack therapy in their procurement and supply, healthcare provider training, and expenditures. This therapy will also help alleviate the symptoms of malaria in neonates.

Artemisinin-resistant malaria.

SUMMARYThe artemisinin antimalarials are the cornerstone of current malaria treatment. The development of artemisinin resistance in Plasmodium falciparum poses a major threat to malaria control and elimination. Recognized first in the Greater Mekong subregion of Southeast Asia nearly 20 years ago, artemisinin resistance has now been documented in Guyana, South America, in Papua New Guinea, and most recently, it has emerged de novo in East Africa (Rwanda, Uganda, South Sudan, Tanzania, Ethiopia, Eritrea, and eastern DRC) where it has now become firmly established. Artemisinin resistance is associated with mutations in the propeller region of the PfKelch gene, which play a causal role, although the parasites' genetic background also makes an important contribution to the phenotype. Clinically, artemisinin resistance manifests as reduced parasiticidal activity and slower parasite clearance and thus an increased risk of treatment failure following artemisinin-based combination therapy (ACT). This results from the loss of artemisinin activity against the younger circulating ring stage parasites. This loss of activity is likely to diminish the life-saving advantage of artesunate in the treatment of severe falciparum malaria. Gametocytocidal and thus transmission blocking activities are also reduced. At current levels of resistance, artemisinin-resistant parasites still remain susceptible at the trophozoite stage of asexual development, and so, artemisinin still contributes to the therapeutic response. As ACTs are the most widely used antimalarial drugs in the world, it is essential from a malaria control perspective that ACT cure rates remain high. Better methods of identifying uncomplicated hyperparasitemia, the main cause of ACT treatment failure, are required so that longer courses of treatment can be given to these high-risk patients. Reducing the use of artemisinin monotherapies will reduce the continued selection pressure which could lead potentially to higher levels of artemisinin resistance. Triple artemisinin combination therapies should be deployed as soon as possible to protect the ACT partner drugs and thereby delay the emergence of higher levels of resistance. As new affordable antimalarial drugs are still several years away, the control of artemisinin resistance must depend on the better use of available tools.

ONT sequencing identifies a high prevalence of crt sensitive, triple mutant dhfr and single mutant dhps parasites within an ANC population in Nigeria.

Malaria in pregnancy is a major public health issue, particularly among vulnerable populations in malaria-endemic sub-Saharan African countries. To mitigate its risks, WHO recommends sulphadoxine-pyrimethamine (SP) for chemoprevention and artemisinin-based combination therapy (ACT) to treat uncomplicated Plasmodium falciparum malaria. These interventions have helped to alleviate the risk associated with malaria in pregnancy; however, in the context of the emergence of SP- and ACT-resistant P. falciparum, maintained efficacy is under threat. Molecular surveillance is a reliable tool to monitor the emergence of resistance where molecular markers are known. Thus, the objective of the study was to use a multiplexed amplicon Oxford Nanopore sequencing approach to assess the molecular markers for antimalarial resistance among pregnant women in Nigeria. Dried blood spots (DBS) were collected from pregnant women who received IPTp-SP at the enrollment and follow-up visits. P. falciparum genomic DNA was extracted by the Chelex® method and Pf18S qPCR was used to detect parasite DNA in each sample. With nested PCR assays, fragments of Pfdhps, Pfdhfr, Pfmdr1, Pfcrt, Pfk13 and Pfama1 genes were amplified and multiplexed amplicon-based sequencing was conducted on the minION Oxford Nanopore Technology. In total, 251 pregnant women were enrolled in the study and 457 DBS samples were collected. P. falciparum genomic DNA was detected in 12% (56/457) of the samples, 31 at baseline and the remaining during the follow-up visits. Pfama1, pfk13, Pfdhps, Pfdhfr, Pfmdr1 and Pfcrt were successfully sequenced in a single run. Notably, k13 artemisinin resistance mutations were absent, the frequencies of Pfdhfr and Pfdhps SP resistance haplotypes, IRN for pyrimethamine resistance and ISGKA/IAGKA associated with sulphadoxine resistance were 82% (36/44) and 64% (27/42), respectively, and the Pfcrt CVIET resistant haplotype was at approximately 22% (7/32). Here a multiplexed amplicon-based ONT assay established that triple mutant Pfdfhr-IRN, double mutant Pfdhps-SG haplotypes and the chloroquine sensitive strain were prevalent among pregnant women in Nigeria.

Frequency of chloroquine-resistant haplotype of Plasmodium falciparum (CVIET) in Ibadan, Southwest Nigeria 17 years post-chloroquine withdrawal

The replacement of chloroquine with artemisinin-based combination therapies (ACTs) for over a decade has had varying impacts on the ability of the malaria parasite to sustain its chloroquine resistance prowess in different malaria-endemic regions. We evaluated the frequency of Plasmodium falciparum chloroquine resistance transporter (PfCRT) mutations in Ibadan, Nigeria 17 years after the replacement of chloroquine with ACTs for malaria treatment. Fragments of PfCRT gene from genomic DNA of microscopically confirmed P. falciparum-infected patients were amplified and sequenced. There were 19% CVIET mutant and 81% CVMNK wild-type haplotypes on residues 72–76. A220S change were found in 16.7% of samples occurring concurrently with the CVIET haplotype, while a Q271E mutation occurred in a PfCRT wild-type isolate. The reduced prevalence of the PfCRT mutant alleles in this study compared to previous reports suggests a gradual disappearance of chloroquine-resistant malaria parasites following reduced drug pressure. It may also be a result of fitness demand on the parasites in attempts to evolve resistance against the current first-line regimen. However, evaluating the prevalence of other chloroquine resistance markers such as Plasmodium falciparum multidrug resistance 1 gene mutations in this population, and a more robust sample size will help to consolidate these findings.

Towards next-generation treatment options to combat Plasmodium falciparum malaria.

Malaria, which is caused by infection of red blood cells with Plasmodium parasites, can be fatal in non-immune individuals if left untreated. The recent approval of the pre-erythrocytic vaccines RTS, S/AS01 and R21/Matrix-M has ushered in hope of substantial reductions in mortality rates, especially when combined with other existing interventions. However, the efficacy of these vaccines is partial, and chemotherapy remains central to malaria treatment and control. For many antimalarial drugs, clinical efficacy has been compromised by the emergence of drug-resistant Plasmodium falciparum strains. Therefore, there is an urgent need for new antimalarial medicines to complement the existing first-line artemisinin-based combination therapies. In this Review, we discuss various opportunities to expand the present malaria treatment space, appraise the current antimalarial drug development pipeline and highlight examples of promising targets. We also discuss other approaches to circumvent antimalarial resistance and how potency against drug-resistant parasites could be retained.

Ligand-based pharmacophore modeling, virtual screening, and molecular dynamics simulations of Pfhsp90 fingerprints in Plasmodium malaria treatment

The World Health Organization (WHO) documents malaria as one of the leading causes of high morbidity and mortality worldwide. The disease affects millions and kills thousands of people annually. Efforts to reduce the global burden of malaria have prompted the WHO to recommend prevention strategies such as using antimalarial drugs. However, these strategies have been ineffective because of antimalarial drug resistance. The only efficacious malaria treatment is Artemisinin-based Combination Therapy (ACT). However, the extended ACT clearance times, linked to the emergence of artemisinin monotherapy resistance recorded most recently in Africa and the Great Mekong region, pose a danger to its efficacy. Therefore, better efficacious antimalarial drugs are required. Since P. falciparum heat shock protein 90 (PfHsp90) is a well-characterized malaria drug target, this study uses it to discover more efficacious antimalarial drugs. An in silico approach was used to discover PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria using a molecular dynamics simulation (MDS) and hierarchical virtual screening. Geldanamycin (GDM), a well-known anti-PfHsp90 compound, was used to identify PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria by screening it against the ZINC20 database via the ZINCPHARMER web server. This virtual screening process resulted in 17 hits. These ZINCPHARMER hits were subjected to drug-likeness and pharmacokinetics properties analysis in the SwissADME web server, and nine of them satisfied the requirements. The nine ZINC20 compounds were docked with PfHsp90 using the PyRx software version 0.8 to understand their interactions. From the molecular docking results, ZINC09060002 (−8.2 kcal/mol), ZINC72133064 (−7.8 kcal/mol), ZINC72163401 (−7.7 kcal/mol), ZINC72358537 (−8.1 kcal/mol), and ZINC72358557 (−7.6 kcal/mol) had better binding affinities to PfHsp90 than GDM (−7.5 kcal/mol). The stability of these molecularly docked protein–inhibitor complexes was assessed through MDS using GROMACS 2022. ZINC72163401, ZINC72358537, and ZINC72358557 formed stable complexes with PfHsp90. The lead compounds were subjected to in vitro validation for their inhibitory capability. They showed promising inhibition of parasite growth with IC50 values ranging between 200 and 400 ng/mL. In this regard, the three PfHsp90 inhibitors can be further developed as potential antimalarial drugs. However, further structural optimization studies and clinical (in vivo) tests are necessary to ascertain the antimalarial activity of these compounds in humans.

Epidemiological, Clinical and Paraclinical Profile of Paediatric Malaria at University Hospital Centre Amissa Bongo in Franceville, Gabon.

Malaria remains the deadliest parasitic disease and continues to cause more than half a million deaths across the world each year, mainly victims are sub-Saharan children. Malaria is a common reason for paediatric hospitalisation. The objective was to characterise malaria and describe the evolution after treatment in the paediatric department of the University Hospital Centre Amissa Bongo de Franceville. This was a cross-sectional study conducted from 1 February 2023 to 15 May 2023. A clinical and biological diagnosis was made in febrile children aged from 6 months to 15 years. A total of 306 patients were included. The mean age was 50.4 ± 44.3 months, 94.3% had consulted within ≥48 h and self-medication was practiced by 83.3%. The prevalence of malaria was 17.3%. Fever ˃39°8C (adjusted odds ratios [aOR] = 2.68; 95% confidence interval [CI] = [1.32-5.48]; P < 0.01), chills (aOR = 2.14; 95% CI = [1.13-4.11]; P < 0.01) and nausea-vomiting (aOR = 2.03; 95% CI = [1.06-3.83]; P = 0.03) were the factors associated with the occurrence of malaria. The majority of children were treated for simple malaria with artemisinin-based combination therapy. A total of 16/53 was seen in post-therapeutic consultation. Of them, 2 patients had a positive thick drop. Non-compliance with preventive measures and the misuse of antimalarials further complicate the clinical picture, requiring parenteral management for the most part.

Analysis of &lt;em&gt;Pfmdr1&lt;/em&gt; and &lt;em&gt;Pfcrt drug&lt;/em&gt; resistant markers in &lt;em&gt;Plasmodium falciparum&lt;/em&gt; following treatments of patients from Nyando and Mbita, Nyanza region with Artemisinin-based combination therapy

The multidrug resistance of Plasmodium falciparum to antimalarial drugs is a major public health concern in the global management of malaria, especially in developing countries. As of today, malaria treatment is primarily dependent on the sustained efficacy of artemisinin-based combination therapy (ACT). Recent reports indicating decline in efficacy of ACT and artesunate monotherapy in Southeast Asia are a major threat to global malaria control achievements. Initially, mutations in Pfmdr1 were associated with chloroquine and amodiaquine resistance only, but there are now emerging field study reports of Pfmdr1 mutation conferring tolerance to ACT. The current study used Restriction Fragment Length Polymorphism to evaluate the prevalence of genetic polymorphisms of Plasmodium falciparum multidrug resistance (Pfmdr1) and Plasmodium falciparum chloroquine-resistant transporter (Pfcrt) gene mutations in Mbita and Nyando field isolates. The findings report that the prevalence of Pfcrt K76T mutation in Plasmodium falciparum field isolates in Mbita declined significantly from 76.3% (95% CI 21.0-31.0) in 2008 to 51.9% (95% CI 19.0-25.0) in 2014, a reduction of 24.4% (χ2df =1 = 4.709, P = 0.0000). In Nyando, prevalence stood at 66.8% (95% CI 12.0-14.0) in 2014 down from 73.7% (95% CI 27.0-48.0), insignificant reduction of 6.9% (χ2df =1 = 17.699, P = 0.0913). Prevalence for Pfmdr1 in Mbita stood at 14.7% (95% CI 44.0-51.0) in 2014 down from 21.9% (95% CI 31.0-49.0) in 2008, a significant reduction of 4.3% (χ2df =1 = 9.011, P = 0.001). While in Nyando, field isolate samples recorded 16.2% (95% CI 22.0-31.0) in 2014, down from 30.6% (95% CI 12.0-27.0), insignificant reduction of 1.9% (χ2df =1 = 11.777, P = 0.0591). Our findings confirm a common trend reported by previous studies: that there has been a small decline in the prevalence of the Pfcrt mutation over a decade since the withdrawal of Chloroquine as the first line of treatment for uncomplicated cases of malaria in Kenya.