Spread Of Antimalarial Resistance Research Articles

Changing Molecular Markers of Antimalarial Drug Sensitivity across Uganda.

The potential spread of antimalarial drug resistance to Africa, in particular for artemisinins and key partner drugs, is a major concern. We surveyed Plasmodium falciparum genetic markers associated with drug sensitivity on 3 occasions at ∼6-month intervals in 2016 and 2017 at 10 sites representing a range of epidemiological settings in Uganda. For putative drug transporters, we found continued evolution toward wild-type sequences associated with increased sensitivity to chloroquine. For pfcrt K76T, by 2017 the prevalence of the wild type was >60% at all sites and >90% at 6 sites. For the pfmdr1 N86Y and D1246Y alleles, wild type prevalence ranged from 80 to 100%. We found low prevalence of K13 propeller domain mutations, which are associated with artemisinin resistance in Asia, but one mutation previously identified in northern Uganda, 675V, was seen in 2.0% of samples, including 5.5% of those from the 3 northernmost sites. Amplification of the pfmdr1 and plasmepsin2 genes, associated elsewhere with decreased sensitivity to lumefantrine and piperaquine, respectively, was seen in <1% of samples. For the antifolate targets pfdhfr and pfdhps, 5 mutations previously associated with resistance were very common, and the pfdhfr 164L and pfdhps 581G mutations associated with higher-level resistance were seen at multiple sites, although prevalence did not clearly increase over time. Overall, changes were consistent with the selective pressure of the national treatment regimen, artemether-lumefantrine, with increased sensitivity to chloroquine, and with poor efficacy of antifolates. Strong evidence for resistance to artemisinins was not seen. Continued surveillance of markers that predict antimalarial drug sensitivity is warranted.

Intermittent Preventive Treatment (IPT): Its Role in Averting Disease-Induced Mortality in Children and in Promoting the Spread of Antimalarial Drug Resistance

We develop an age-structured ODE model to investigate the role of intermittent preventive treatment (IPT) in averting malaria-induced mortality in children, and its related cost in promoting the spread of antimalarial drug resistance. IPT, a malaria control strategy in which a full curative dose of an antimalarial medication is administered to vulnerable asymptomatic individuals at specified intervals, has been shown to reduce malaria transmission and deaths in children and pregnant women. However, it can also promote drug resistance spread. Our mathematical model is used to explore IPT effects on drug resistance and deaths averted in holoendemic malaria regions. The model includes drug-sensitive and drug-resistant strains as well as human hosts and mosquitoes. The basic reproduction, and invasion reproduction numbers for both strains are derived. Numerical simulations show the individual and combined effects of IPT and treatment of symptomatic infections on the prevalence of both strains and the number of lives saved. Our results suggest that while IPT can indeed save lives, particularly in high transmission regions, certain combinations of drugs used for IPT and to treat symptomatic infection may result in more deaths when resistant parasite strains are circulating. Moreover, the half-lives of the treatment and IPT drugs used play an important role in the extent to which IPT may influence spread of the resistant strain. A sensitivity analysis indicates the model outcomes are most sensitive to the reduction factor of transmission for the resistant strain, rate of immunity loss, and the natural clearance rate of sensitive infections.

A Pilot Study on Antimalarial Effects of Moringa oleifera Leaf Extract in Plasmodium berghei Infection in Mice

The emergence and spread of antimalarial drug resistance of Plasmodium parasites, as well as hypoglycemia, during malaria infection, and subsequent death, are critical problems in malaria-endemic areas. Hence, finding new compounds, especially plant extracts having antimalarial and anti-hypoglycemic activities, are urgently needed. The present study aimed to investigate the antimalarial and anti-hypoglycemic effects of Moringa oleifera leaf extract in Plasmodium berghei infection in mice. Aqueous crude extract of M. oleifera leaves was freshly prepared and used for an efficacy test in vivo. Groups of ICR mice (5 mice in each) were infected with 1´107 infected red blood cells of P. berghei ANKA by intraperitoneal injection and given the extract orally with doses of 100, 500, and 1000 mg/kg for 4 consecutive days. Parasitemia and plasma glucose levels were subsequently measured. The results showed that M. oleifera leaf extract presented significant (p &lt; 0.001) inhibition of parasitemia in a dose-dependent manner. Moreover, this extract exerted anti-hypoglycemia effects in infected mice in a dose-dependent manner. The highest degrees of activity were found at a dose of 1000 mg/kg of the extract. Additionally, no effect on plasma glucose was found in normal mice treated with this extract. It can be concluded that aqueous crude extract of M. oleifera leaves exerted antimalarial and anti-hypoglycemic effects in P. berghei infection in mice.

High throughput resistance profiling of Plasmodium falciparum infections based on custom dual indexing and Illumina next generation sequencing-technology

Genetic polymorphisms in P. falciparum can be used to indicate the parasite’s susceptibility to antimalarial drugs as well as its geographical origin. Both of these factors are key to monitoring development and spread of antimalarial drug resistance. In this study, we combine multiplex PCR, custom designed dual indexing and Miseq sequencing for high throughput SNP-profiling of 457 malaria infections from Guinea-Bissau, at the cost of 10 USD per sample. By amplifying and sequencing 15 genetic fragments, we cover 20 resistance-conferring SNPs occurring in pfcrt, pfmdr1, pfdhfr, pfdhps, as well as the entire length of pfK13, and the mitochondrial barcode for parasite origin. SNPs of interest were sequenced with an average depth of 2,043 reads, and bases were called for the various SNP-positions with a p-value below 0.05, for 89.8–100% of samples. The SNP data indicates that artemisinin resistance-conferring SNPs in pfK13 are absent from the studied area of Guinea-Bissau, while the pfmdr1 86 N allele is found at a high prevalence. The mitochondrial barcodes are unanimous and accommodate a West African origin of the parasites. With this method, very reliable high throughput surveillance of antimalarial drug resistance becomes more affordable than ever before.

Exploring the role of socioeconomic factors in the development and spread of anti-malarial drug resistance: a qualitative study

BackgroundMalaria remains a global health issue with the burden unevenly distributed to the disadvantage of the developing countries of the world. Poverty contributes to the malaria burden as it has the ability to affect integral aspects of malaria control. There have been renewed efforts in the global malaria control, resulting in reductions in the global malaria burden over the last decade. However, the development of resistance to artemisinin-based combination therapy threatens the sustainability of the present success in malaria control. Anti-malarial drug use practices/behaviours remain very important drivers of drug resistance. This study adopted a social epidemiological stance in exploring the underlying socioeconomic factors that determine drug use behaviours promoting anti-malarial drug resistance.MethodsA qualitative approach, involving the use of interviews, was used in this inquiry to explore the existing anti-malarial drug use practices in the Nigerian population; and the different socioeconomic factors influencing the behaviours.ResultsThe significant malaria treatment behaviours influenced by socioeconomic factors in this study were the practice of ‘mixing’ drugs for malaria treatment, presumptive treatment, sharing of malaria treatment course, and the use of anti-malaria monotherapies. All the rural dwellers in this study reported they have mixed drugs for malaria treatment. When symptoms were experienced, socio-economic factors, like type of settlement, income level and occupation, tended to determine the treatment behaviour and, therefore, informed and determined the experience of the illness.DiscussionSocial and economic contexts can influence behaviours as they contribute in shaping norms and in creating opportunities that promote certain behaviours. As shown in this study, income level and type of settlement, as structural factors, affect the decision on where to seek malaria treatment and whether or not a malaria diagnostic test will be used prior to treatment. One of the dangers of using the mixed anti-malarial drugs is that it offers a safe route for the sale of expired and fake anti-malarial drugs as the mixed drugs are not sold or dispensed in their original packets.Conclusions and recommendationsPopulation-wide improvements in income, education, environmental and structural conditions of rural dwellers in malaria-endemic settings will encourage behavioural change on how anti-malarial drugs are used.

Domestic trends in malaria research and development in China and its global influence

BackgroundThough many countries, including China, are moving towards malaria elimination, malaria remains a major global health threat. Due to the spread of antimalarial drug resistance and the need for innovative medical products during the elimination phase, further research and development (R&D) of innovative tools in both epidemic and elimination areas is needed. This study aims to identify the trends and gaps in malaria R&D in China, and aims to offer suggestions on how China can be more effectively involved in global malaria R&D.MethodsQuantitative analysis was carried out by collecting data on Chinese malaria-related research programmes between 1985 and 2014, invention patents in China from 1985 to 2014, and articles published by Chinese researchers in PubMed and Chinese databases from 2005 to 2014. All data were screened and extracted for numerical analysis and were categorized into basic sciences, drug/drug resistance, immunology/vaccines, or diagnostics/detection for chronological and subgroup comparisons.ResultsThe number of malaria R&D activities have shown a trend of increase during the past 30 years, however these activities have fluctuated within the past few years. During the past 10 years, R&D on drug/drug resistance accounted for the highest percentages of research programmes (32.4%), articles (55.0% in PubMed and 50.6% in Chinese databases) and patents (45.5%). However, these R&D activities were mainly related to artemisinin. R&D on immunology/vaccines has been a continuous interest for China’s public entities, but the focus remains on basic science. R&D in the area of high-efficiency diagnostics has been rarely seen or reported in China.ConclusionsChina has long been devoted to malaria R&D in multiple areas, including drugs, drug resistance, immunology and vaccines. R&D on diagnostics has received significantly less attention, however, it should also be an area where China can make a contribution. More focus on malaria R&D is needed, especially in the area of diagnostics, if China would like to contribute in a more significant way to global malaria control and elimination.

Emerging polymorphisms in falciparum Kelch 13 gene in Northeastern region of India.

BackgroundRecent reports of emergence and spread of artemisinin resistance in the Southeast Asia region, including Myanmar, pose a greater threat to malaria control and elimination in India. Whole genome sequencing studies have associated mutations in the K13 propeller gene (k13), PF3D7_1343700 with artemisinin resistance both in vitro and in vivo. The aim of the present study was to find the k13 gene polymorphisms in Plasmodium falciparum parasites from the three sites in the Northeast region of India, bordering Bangladesh and Myanmar.MethodsA total of 254 samples collected during 2014–2015 from Tripura, Mizoram and Arunachal Pradesh states in the Northeast region of India were used to obtain the full-length k13 gene sequences.ResultsThree non-synonymous (NS) mutations: two in the propeller region, namely at codon 446 and 578, were observed besides one at codon 189 in the non-propeller region. The treatment outcome was not affected by these mutations at any of the sites. In addition, microsatellite variation in the N-terminus of the k13 protein was observed at all the study sites.ConclusionThis is the first study to document the presence of F446I NS mutation in the k13 propeller region from Changlang district, Arunachal Pradesh, a site adjoining the Indo-Myanmar border region, where this mutation is highly prevalent. In addition, NS mutation A578S has been observed only at Lunglei district, Mizoram, a site bordering Bangladesh and K189T mutation with relatively higher frequency in Mizoram and Tripura states. The presence of F446I mutation in a region close to the Myanmar border is notable. Considering the spread of anti-malarial drug resistance from Southeast Asia to the Northeast region of India in the past, there is an urgent need to undertake systematic mapping studies to ascertain the role and extent of this mutation in artemisinin resistance in this region of country.

Polymorphisms in K13, pfcrt, pfmdr1, pfdhfr, and pfdhps in parasites isolated from symptomatic malaria patients in Burkina Faso.

Background: The emergence of resistance to artemisinin derivatives in western Cambodia is threatening to revert the recent advances made toward global malaria control and elimination. Known resistance-mediating polymorphisms in the K13, pfcrt, pfmdr1, pfdhfr, and pfdhps genes are of greatest importance for monitoring the spread of antimalarial drug resistance. Methods: Samples for the present study were collected from 244 patients with uncomplicated malaria in health centers of Bobo-Dioulasso, Burkina Faso. Blood sample was collected on filter paper before the subject received any treatment. The parasite DNA was then extracted and amplified by Polymerase Chain Reaction (PCR) to evaluate the prevalence of polymorphism of pfcrtK76T, pfmdr1 (N86Y, Y184F), and pfdhps (A437G, K540E). The K13 gene polymorphism was analyzed by nested PCR followed by sequencing. Results: The overall results showed 2.26% (5/221) of K13 synonymous mutant alleles (two C469C, one Y493Y, one G496G, and one V589V), 24.78%, 19.58%, 68.75%, 60.9%, 53.7%, 63.8%, and 64.28%, respectively, for mutant pfcrt 76T, pfmdr1-86Y, pfmdr1-184F, pfdhfr51I, pfdhfr59R, pfdhfr108N, and pfdhps 437G. We did not report any mutation at codon 540 of pfdhps. Conclusion: These results provide baseline prevalence of known drug resistance polymorphisms and suggest that artemisinin combination therapies may retain good efficacy in the treatment of uncomplicated malaria in Burkina Faso.

Reduced deformability of parasitized red blood cells as a biomarker for anti-malarial drug efficacy.

BackgroundMalaria remains a challenging and fatal infectious disease in developing nations and the urgency for the development of new drugs is even greater due to the rapid spread of anti-malarial drug resistance. While numerous parasite genetic, protein and metabolite biomarkers have been proposed for testing emerging anti-malarial compounds, they do not universally correspond with drug efficacy. The biophysical character of parasitized cells is a compelling alternative to these conventional biomarkers because parasitized erythrocytes become specifically rigidified and this effect is potentiated by anti-malarial compounds, such as chloroquine and artesunate. This biophysical biomarker is particularly relevant because of the mechanistic link between cell deformability and enhanced splenic clearance of parasitized erythrocytes.MethodsRecently a microfluidic mechanism, called the multiplexed fluidic plunger that provides sensitive and rapid measurement of single red blood cell deformability was developed. Here it was systematically used to evaluate the deformability changes of late-stage trophozoite-infected red blood cells (iRBCs) after treatment with established clinical and pre-clinical anti-malarial compounds.ResultsIt was found that rapid and specific iRBC rigidification was a universal outcome of all but one of these drug treatments. The greatest change in iRBC rigidity was observed for (+)-SJ733 and NITD246 spiroindolone compounds, which target the Plasmodium falciparum cation-transporting ATPase ATP4. As a proof-of-principle, compounds of the bisindole alkaloid class were screened, where cladoniamide A was identified based on rigidification of iRBCs and was found to have previously unreported anti-malarial activity with an IC50 lower than chloroquine.ConclusionThese results demonstrate that rigidification of iRBCs may be used as a biomarker for anti-malarial drug efficacy, as well as for new drug screening. The novel anti-malarial properties of cladoniamide A were revealed in a proof-of-principle drug screen.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0957-z) contains supplementary material, which is available to authorized users.

Disagreement in genotyping results of drug resistance alleles of the Plasmodium falciparum dihydrofolate reductase (Pfdhfr) gene by allele-specific PCR (ASPCR) assays and Sanger sequencing.

The rapid spread of antimalarial drug resistance in Plasmodium falciparum over the past few decades has necessitated intensive monitoring of such resistance for an effective malaria control strategy. P. falciparum dihydropteroate synthase (Pfdhps) and P. falciparum dihydrofolate reductase (Pfdhfr) genes act as molecular markers for resistance against the antimalarial drugs sulphadoxine and pyrimethamine, respectively. Resistance to pyrimethamine which is used as a partner drug in artemisinin combination therapy (ACT) is associated with several mutations in the Pfdhfr gene, namely A16V, N51I, C59R, S108N/T and I164L. Therefore, routine monitoring of Pfdhfr-drug-resistant alleles in a population may help in effective drug resistance management. Allele-specific PCR (ASPCR) is one of the commonly used methods for molecular genotyping of these alleles. In this study, we genotyped 55 samples of P. falciparum for allele discrimination at four codons of Pfdhfr (N51, C59, S108 and I164) by ASPCR using published methods and by Sanger's DNA sequencing method. We found that the ASPCR identified a significantly higher number of mutant alleles as compared to the DNA sequencing method. Such discrepancies arise due to the non-specificity of some of the allele-specific primer sets and due to the lack of sensitivity of Sanger's DNA sequencing method to detect minor alleles present in multiple clone infections. This study reveals the need of a highly specific and sensitive method for genotyping and detecting minor drug-resistant alleles present in multiple clonal infections.

Malaria and the mobile and migrant population in Cambodia: a population movement framework to inform strategies for malaria control and elimination.

BackgroundThe relationships between human population movement (HPM) and health are a concern at global level. In the case of malaria, those links are crucial in relation to the spread of drug resistant parasites and to the elimination of malaria in the Greater Mekong sub-Region (GMS) and beyond. The mobile and migrant populations (MMP) who are involved in forest related activities are both at high risk of being infected with malaria and at risk of receiving late and sub-standard treatment due to poor access to health services. In Cambodia, in 2012, the National Malaria Control Programme (NMCP) identified, as a key objective, the development of a specific strategy for MMPs in order to address these challenges. A population movement framework (PMF) for malaria was developed and operationalized in order to contribute to this strategy.MethodsA review of the published and unpublished literature was conducted. Based on a synthesis of the results, information was presented and discussed with experienced researchers and programme managers in the Cambodian NMCP and led to the development and refinement of a PMF for malaria. The framework was “tested” for face and content validity with national experts through a workshop approach.ResultsIn the literature, HPM has been described using various spatial and temporal dimensions both in the context of the spread of anti-malarial drug resistance, and in the context of malaria elimination and previous classifications have categorized MMPs in Cambodia and the GMS through using a number of different criteria. Building on these previous models, the PMF was developed and then refined and populated with in-depth information relevant to Cambodia collected from social science research and field experiences in Cambodia. The framework comprises of the PMF itself, MMP activity profiles and a Malaria Risk Index which is a summation of three related indices: a vulnerability index, an exposure index and an access index which allow a qualitative ranking of malaria risk in the MMP population. Application of currently available data to the framework illustrates that the highest risk population are those highly mobile populations engaged in forest work.ConclusionThis paper describes the process of defining MMPs in Cambodia, identifying the different activities and related risks to appropriately target and tailor interventions to the highest risk groups. The framework has been used to develop more targeted behaviour change and outreach interventions for MMPs in Cambodia and its utility and effectiveness will be evaluated as part of those interventions.

Polymorphisms in the K13-propeller gene in artemisinin-susceptible Plasmodium falciparum parasites from Bougoula-Hameau and Bandiagara, Mali.

Artemisinin-resistant Plasmodium falciparum malaria has been documented in southeast Asia and may already be spreading in that region. Molecular markers are important tools for monitoring the spread of antimalarial drug resistance. Recently, single-nucleotide polymorphisms (SNPs) in the PF3D7_1343700 kelch propeller (K13-propeller) domain were shown to be associated with artemisinin resistance in vivo and in vitro. The prevalence and role of K13-propeller mutations are poorly known in sub-Saharan Africa. K13-propeller mutations were genotyped by direct sequencing of nested polymerase chain reaction (PCR) amplicons from dried blood spots of pre-treatment falciparum malaria infections collected before and after the use of artemisinin-based combination therapy (ACT) as first-line therapy in Mali. Although K13-propeller mutations previously associated with delayed parasite clearance in Cambodia were not identified, 26 K13-propeller mutations were identified in both recent samples and pre-ACT infections. Parasite clearance time was comparable between infections with non-synonymous K13-propeller mutations and infections with the reference allele. These findings suggest that K13-propeller mutations are present in artemisinin-sensitive parasites and that they preceded the wide use of ACTs in Mali.

Malaria policies versus practices, a reality check from Kinshasa, the capital of the Democratic Republic of Congo.

BackgroundArtemisinin-based combination therapy (ACT) following a confirmed parasitological diagnosis is recommended by the World Health Organization (WHO) and the Congolese National Malaria Control Program (NMCP). However, commitment and competence of all stakeholders (patients, medical professionals, governments and funders) is required to achieve effective case management and secure the “useful therapeutic life” of the recommended drugs. The health seeking behaviour of patients and health care professionals’ practices for malaria management were assessed.MethodsThis was an observational study embedded in a two-stage cluster randomized survey conducted in one health centre (HC) in each of the 12 selected health zones in Kinshasa city. All patients with clinical malaria diagnosis were eligible. Their health seeking behaviour was recorded on a specific questionnaire, as well as the health care practitioners’ practices. The last were not aware that their practices would be assessed.ResultsSix hundred and twenty four patients were assessed, of whom 136 (21.8%) were under five years. Three hundred and thirty five (55%) had taken medication prior to the current consultation (self -medication with any product or visiting another HC) of whom 47(14%) took an antimalarial drug, and 56 (9%) were treated presumptively. Among those, 53.6% received monotherapy either with quinine, artesunate, phytomedicines, sulfadoxine-pyrimethamine or amodiaquine. On the other side, when clinicians were informed about laboratory results, monotherapy was prescribed in 39.9% of the confirmed malaria cases. Only 285 patients (45.7%) were managed in line with WHO and NMCP guidelines, of whom 120 (19.2%) were prescribed an ACT after positive blood smear and 165 (26.4%) received no antimalarial after a negative result.ConclusionThis study shows the discrepancy between malaria policies and the reality on the field in Kinshasa, regarding patients’ health seeking behaviour and health professionals’ practices. Consequently, the poor compliance to the policies may contribute to the genesis and spread of antimalarial drug resistance and also have a negative impact on the burden of the disease.

High prevalence of pfdhfr–pfdhps triple mutations associated with anti-malarial drugs resistance in Plasmodium falciparum isolates seven years after the adoption of sulfadoxine–pyrimethamine in combination with artesunate as first-line treatment in Iran

The spread of anti-malarial drug resistance will challenge any malaria control and elimination strategies, and routine monitoring of resistance-associated molecular markers of commonly used anti-malarial drugs is very important. Therefore, in the present investigation, the extent of mutations/haplotypes in dhfr and dhps genes of Plasmodium falciparum isolates (n=72) was analyzed seven years after the introduction of sulfadoxine–pyrimethamine (SP) plus artesunate (AS) as first-line anti-malarial treatment in Iran using PCR–RFLP methods. The results showed that the majority of the patients (97.2%) carried both 59R and 108N mutations in pure form with wild-type genotype at positions N51 and I164. Additionally, a significant increase (P<0.05) was observed in the frequency of R59N108/G437 haplotype (79.2%) during 2012–2014. This raise was because of the significant increase (P<0.05) in the frequency of 437G mutation (81.9%), which more likely was due to more availability of SP as anti-malarial drug for treatment of falciparum patients in these malaria-endemic areas of Iran. However, no quintuple mutations associated with treatment failure were detected. In conclusion, the present results along with in vivo assays suggest that seven years after the adoption of SP–AS as the first-line treatment in Iran, this drug remains efficacious for treatment of uncomplicated falciparum malaria, as a partner drug with AS in these malaria-endemic areas.

The effect of intermittent preventive treatment on anti-malarial drug resistance spread in areas with population movement.

BackgroundThe use of intermittent preventive treatment in pregnant women (IPTp), children (IPTc) and infant (IPTi) is an increasingly popular preventive strategy aimed at reducing malaria risk in these vulnerable groups. Studies to understand how this preventive intervention can affect the spread of anti-malarial drug resistance are important especially when there is human movement between neighbouring low and high transmission areas. Because the same drug is sometimes utilized for IPTi and for symptomatic malaria treatment, distinguishing their individual roles on accelerating the spread of drug resistant malaria, with or without human movement, may be difficult to isolate experimentally or by analysing data. A theoretical framework, as presented here, is thus relevant as the role of IPTi on accelerating the spread of drug resistance can be isolated in individual populations and when the populations are interconnected and interact.MethodsA previously published model is expanded to include human movement between neighbouring high and low transmission areas, with focus placed on the malaria parasites. Parasite fitness functions, determined by how many humans the parasites can infect, are used to investigate how fast resistance can spread within the neighbouring communities linked by movement, when the populations are at endemic equilibrium.ResultsModel simulations indicate that population movement results in resistance spreading fastest in high transmission areas, and the more complete the anti-malarial resistance the faster the resistant parasite will tend to spread through a population. Moreover, the demography of infection in low transmission areas tends to change to reflect the demography of high transmission areas. Additionally, when regions are strongly connected the rate of spread of partially resistant parasites (R1) relative to drug sensitive parasites (RS), and fully resistant parasites (R2) relative to partially resistant parasites (R1) tend to behave the same in both populations, as should be expected.ConclusionsIn fighting anti-malarial drug resistance, different drug resistance monitoring and management policies are needed when the area in question is an isolated high or low transmission area, or when it is close and interacting with a neighbouring high or low transmission area, with human movement between them.Electronic supplementary materialThe online version of this article (doi:10.1186/1475-2875-13-428) contains supplementary material, which is available to authorized users.

Strategic use of antimalarial drugs that block falciparum malaria parasite transmission to mosquitoes to achieve local malaria elimination.

The ultimate aim of malaria chemotherapy is not only to treat symptomatic infection but also to reduce transmission potential. With the absence of clinically proven vaccines, drug-mediated blocking of malaria transmission gains growing interest in the research agenda for malaria control and elimination. In addition to the limited arsenal of antimalarials available, the situation is further complicated by the fact that most commonly used antimalarials are being extensively resisted by the parasite and do not assist in blocking its transmission to vectors. Most antimalarials do not exhibit gametocytocidal and/ or sporontocidal activity against the sexual stages of Plasmodium falciparum but may even enhance gametocytogenesis and gametocyte transmissibility. Artemisinin derivatives and 8-aminoquinolines are useful transmission-blocking antimalarials whose optimal actions are on different stages of gametocytes. Transmission control interventions that include gametocytocides covering the spectrum of gametocyte development should be used to reduce and, if possible, stop transmission and infectivity of gametocytes to mosquitoes. Potent gametocytocidal drugs could also help deter the spread of antimalarial drug resistance. Novel proof-of-concept compounds with gametocytocidal activity, such as trioxaquines, synthetic endoperoxides, and spiroindolone, should be further tested for possible clinical utility before investigating the possibility of integrating them in transmission-reducing interventions. Strategic use of potent gametocytocides at appropriate timing with artemisinin-based combination therapies should be given attention, at least, in the short run. This review highlights the role that antimalarials could play in blocking gametocyte transmission and infectivity to mosquitoes and, hence, in reducing the potential of falciparum malaria transmissibility and drug resistance spread.

Mixed 2D–3D-LQTA-QSAR study of a series of Plasmodium falciparum dUTPase inhibitors

The spread of antimalarial drug resistance and lack of effective vaccines into consideration drive significant role to develop novel antimalarial agents for the treatment of malaria. The Plasmodium falciparum deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) has been identified as a promising target for new drug development. In this study, we report a receptor-dependent mixed 2D- and 3D-QSAR model using the LQTA-QSAR methodology on a series of dUTPase inhibitors. QSAR models were constructed by a training set of 55 compounds with specific stereochemistry and an external set of 18. The model satisfied a set of rigorous validation criteria and performed well in the prediction of an external test set. The proposed model also checked for free from chance correlation, reliability, and robustness by y-randomization and leave-N-out tests. Final model provided the following statistics (R 2 = 0.85, Q LOO 2 = 0.78 and Q ext 2 = 0.76) with only 12 descriptors and 3 latent variables. We showed that a combination of 2D classic and 3D molecular field descriptors could lead to relevant QSAR models, that in comparison with model solely generated by 3D descriptors has improved and illustrated more robustness and prediction ability. Visualization of the descriptors of the best model helps us to interpret the model from the chemical point of view, supporting the applicability of this new approach in rational drug design.

Mitigating the Spread of Antimalarial Drug Resistance and Sustaining the Achievements in Malaria-Eliminating Countries

Global efforts at controlling malaria have resulted in significant successes in reducing malaria prevalence in many endemic countries. As a result, Cotter and colleagues highlighted the changing trends in malaria as countries approach elimination [1]. The efforts in controlling malaria have led to a decrease in global malaria incidence and mortality, and the decrease is even more impressive in malariaeliminating countries [2]. Cotter and colleagues however raised the concern that traditional control interventions are likely to be less effective due to the changing epidemiology, and detailed the need for very important strategies that must be adopted in order to continue shrinking the malaria map. However, the concern of resistance to antimalarial drug, especially artemisinin, has not been sufficiently raised and discussed in the concept of the changing epidemiology. Carrara et al. [3] pointed out that resistance to artemisinin could trigger a catastrophic resurgence in malaria in many parts of the world where significant reductions in malaria morbidity and mortality have been attained.

The impact of heterogeneous transmission on the establishment and spread of antimalarial drug resistance

Despite the important insights gained by extending the classical models of malaria, other factors, such as immunity, heterogeneous biting, and differential patterns of drug use have not been fully explored due to the complexity of modeling multiple simultaneous malaria infections competing within a host. Understanding these factors is important for understanding how to control the spread of drug resistance to artemisinin which is just emerging in Southeast Asia. The emergence of resistance plays out at the population level, but is the result of competition within individuals for transmission events. Most studies of drug resistance evolution have focused on transmission between hosts and ignored the role of within-host competition due to the inherent complexity of modeling at multiple scales. To embed within-host competition in the model, we used an agent-based framework that was developed to understand how deviations from the classical assumptions of the Ross-MacDonald type models, which have been well-described and analyzed, impact the dynamics of disease. While structured to be a stochastic analog to classical Ross-Macdonald type models, the model is nonetheless based on individuals, and thus aspects of within-host competition can be explored. We use this framework to explore the role of heterogeneous biting and transmission on the establishment and spread of resistance in a population. We find that heterogeneous transmission slows the establishment of resistance in a population, but once resistance is established, it speeds the spread of resistance through the population. These results are due to the skewed distribution of biting which makes onward transmission a low probability and suggests that targeting the “core” group of individuals that provide the vast majority of bites could significantly slow the spread of resistance.

Case management of malaria: Treatment and chemoprophylaxis

Malaria case management is a vital component of programmatic strategies for malaria control and elimination. Malaria case management encompasses prompt and effective treatment to minimise morbidity and mortality, reduce transmission and prevent the emergence and spread of antimalarial drug resistance. Malaria is an acute illness that may progress rapidly to severe disease and death, especially in non-immune populations, if not diagnosed early and promptly treated with effective drugs. In this article, the focus is on malaria case management, addressing treatment, monitoring for parasite drug resistance, and the impact of drug resistance on treatment policies; it concludes with chemoprophylaxis and treatment strategies for malaria elimination in South Africa.