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Currently recommended methods of assessing the efficacy of uncomplicated falciparum malaria treatment work less well in high-transmission than in low-transmission settings. There is also uncertainty how to assess intermittent preventive therapies and seasonal malaria chemoprevention (SMC), and Plasmodium vivax radical cure. A pharmacometric antimalarial resistance monitoring (PARM) approach is proposed specifically for evaluating slowly eliminated antimalarial drugs in areas of high transmission. In PARM antimalarial drug concentrations at recurrent parasitaemia are measured to identify outliers (i.e., recurrent parasitaemias in the presence of normally suppressive drug concentrations) and to evaluate changes over time. PARM requires characterization of pharmacometric profiles but should be simpler and more sensitive than current molecular genotyping-based methodologies. PARM does not require parasite genotyping and can be applied to the assessment of both prevention and treatment.

Plasmodium falciparum causes malaria, and its resistance to artemisinin (ART) - a drug used for managing malaria - threatens to interfere with the effective control of malaria. ART resistance (ARTr) is driven by increased tolerance to oxidative stress and reduced haemoglobin trafficking to the food vacuole. We discuss how extracellular vesicles (EVs) may play a role in developing ARTr.

Recent progress in genomics and molecular genetics has empowered novel approaches to closely study gene functions in disease-causing pathogens. In the human malaria parasite Plasmodium falciparum, the application of genome-based analyses, site-directed genome editing, and genetic systems that allow for temporal and quantitative regulation of gene and protein expression have been invaluable in defining the genetic basis of antimalarial resistance and elucidating candidate targets to accelerate drug discovery efforts. Using examples from recent studies, we review applications of some of these approaches in advancing our understanding of Plasmodium biology and illustrate their contributions and limitations in characterizing parasite genomic loci associated with antimalarial drug responses.

Malaria remains a heavy public health and socioeconomic burden in tropical and subtropical regions. Increasing resistance against front-line treatments implies that novel targets for antimalarial intervention are urgently required. Protein kinases of both the parasites and their host cells possess strong potential in this respect. We present an overview of the updated kinome of Plasmodium falciparum, the species that is the largest contributor to malaria mortality, and of current knowledge pertaining to the function of parasite-encoded protein kinases during the parasite's life cycle. Furthermore, we detail recent advances in drug initiatives targeting Plasmodium kinases and outline the potential of protein kinases in the context of the growing field of host-directed therapies, which is currently being explored as a novel way to combat parasite drug resistance.

Recent gains in the fight against malaria are threatened by the emergence and spread of artemisinin and partner drug resistance in Plasmodium falciparum in the Greater Mekong Subregion (GMS). When artemisinins are combined with a single partner drug, all recommended artemisinin-based combination therapies have shown reduced efficacy in some countries in the GMS at some point. Novel drugs are not available for the near future. Triple artemisinin-based combination therapies, combining artemisinins with two currently available partner drugs, will provide one of the last remaining safe and effective treatments for falciparum malaria that can be deployed rapidly in the GMS, whereas their deployment beyond the GMS could delay or prevent the global emergence and spread of resistance to currently available drugs.

Resistance to the artemisinin derivatives, our most effective antimalarial drugs, has not manifest as a classical resistance phenotype in which parasites can tolerate higher drug concentrations. Instead, resistant parasites have an altered maturation. We hypothesize that the short half-life of artemisinin concentrations is an unanticipated driver of this novel resistance phenotype.

Artemisinin and its derivatives (ART) are crucial first-line antimalarial drugs that rapidly clear parasitemia, but recrudescences of the infection frequently follow ART monotherapy. For this reason, ART must be used in combination with one or more partner drugs that ensure complete cure. The ability of malaria parasites to survive ART monotherapy may relate to an innate growth bistability phenomenon whereby a fraction of the drug-exposed population enters into metabolic quiescence (dormancy) as persister forms. Characterization of the events that underlie entry and waking from persistence may lead to lasting breakthroughs in malaria chemotherapy that can prevent recrudescences and protect the future of ART-based combination therapies.

Artemisinins - the frontline antimalarial drug class - are compromised by emerging resistance, putting at risk the lives of hundreds of thousands of people each year. Resistance is associated with mutations in a malaria parasite protein, called Kelch 13 (K13). Recent work suggests that K13 is located at the cytostome (cell mouth) that the parasite uses to take up hemoglobin. Here we explore the proposal that K13 mutations confer artemisinin resistance by dampening hemoglobin endocytosis. This model suggests that the resultant decrease in hemoglobin-derived heme reduces artemisinin activation, which is sufficient to enable parasite survival in the early ring stage of infection. A fuller understanding of the resistance mechanism will underpin efforts to develop alternative antimalarial strategies.

Preventing human-to-mosquito transmission of malaria parasites provides possible solutions to interrupt the malaria parasite life cycle for malaria elimination. The development of validated routine assays enabled the discovery of such transmission-blocking compounds. Currently, one development priority remains on combinations of dual-active compounds with equipotent activity against both the disease-causing asexual and transmissible, sexual erythrocytic stages. Additionally, transmission-blocking compounds that target gametocyte-specific biology could be used in combination with compounds against asexual parasites. In either case, preventing transmission will reduce the risk of reinfection and, if different processes are targeted, also curb the spread of drug resistance. Here, we provide an updated roadmap to the discovery and development of new antimalarials with transmission-blocking activity to guide drug discovery for malaria elimination.

Strategies to counteract or prevent emerging drug resistance are crucial for the design of next-generation antimalarials. In the past, resistant parasites were generally identified following treatment failures in patients, and compounds would have to be abandoned late in development. An early understanding of how candidate therapeutics lose efficacy as parasites evolve resistance is important to facilitate drug design and improve resistance detection and monitoring up to the postregistration phase. We describe a new strategy to assess resistance to antimalarial compounds as early as possible in preclinical development by leveraging tools to define the Plasmodium falciparum resistome, predict potential resistance risks of clinical failure for candidate therapeutics, and inform decisions to guide antimalarial drug development.

© 2018 Elsevier Ltd Molecular surveillance of antimalarial drug resistance markers has become an important part of resistance detection and containment. In the current climate of multidrug resistance, including resistance to the global front-line drug artemisinin, there is a consensus to upscale molecular surveillance. The most salient limitation to current surveillance efforts is that skill and infrastructure requirements preclude many regions. This includes sub-Saharan Africa, where Plasmodium falciparum is responsible for most of the global malaria disease burden. New molecular and data technologies have emerged with an emphasis on accessibility. These may allow surveillance to be conducted in broad settings where it is most needed, including at the primary healthcare level in endemic countries, and extending to the village health worker.

Artemisinin (ART)-based combination therapies are the most efficacious treatment of uncomplicated Plasmodium falciparum malaria. Alarmingly, P. falciparum strains have acquired resistance to ART across much of Southeast Asia. ART creates widespread protein and lipid damage inside intraerythrocytic parasites, necessitating macromolecule degradation. The proteasome is the main engine of Plasmodium protein degradation. Indeed, proteasome inhibition and ART have shown synergy in ART-resistant parasites. Moreover, ubiquitin modification is associated with altered parasite susceptibility to multiple antimalarials. Targeting the ubiquitin-proteasome system (UPS), therefore, is an attractive avenue to combat drug resistance. Here, we review recent advances leading to specific targeting of the Plasmodium proteasome. We also highlight the potential for targeting other nonproteasomal protein degradation systems as an additional strategy to disrupt protein homeostasis.

Rapid emergence of resistance to atovaquone, which targets electron transport in the malaria parasite mitochondrion, relegated its use to prophylaxis and even cast a shadow over the development of drugs targeting other parasite mitochondrial pathways. Here we argue for a renewed focus on the mitochondrion as a drug target, focusing particularly on the issues of resistance. We posit a hypothesis for why atovaquone resistance emerges so quickly, and we explain how facile acquisition of resistance is apparently offset by an inability of parasites to spread this resistance. We also explore the utility and resistance issues for emerging new drugs targeting parasite mitochondria, concluding that the mitochondrion is indeed an excellent target.

Mathematical models of the dynamics of a drug within the host are now frequently used to guide drug development. These generally focus on assessing the efficacy and duration of response to guide patient therapy. Increasingly, antimalarial drugs are used at the population level, to clear infections, provide chemoprevention, and to reduce onward transmission of infection. However, there is less clarity on the extent to which different drug properties are important for these different uses. In addition, the emergence of drug resistance poses new threats to longer-term use and highlights the need for rational drug development. Here, we argue that integrating within-host pharmacokinetic and pharmacodynamic (PK/PD) models with mathematical models for the population-level transmission of malaria is key to guiding optimal drug design to aid malaria elimination., Trends Antimalarial drugs are being used in many different contexts beyond treatment of disease – increasingly with the aim of reducing malaria transmission in a community. Each drug has different attributes – killing efficacy against asexual parasites, duration of effect, gametocytocidal activity, mosquitocidal activity, liver-stage activity (for Plasmodium vivax), dosing schedule and toxicity. Drug attributes need to be rationally combined to match their usage aims based on a quantitative understanding of their properties. For transmission reductions, the individual patient approach is less relevant and a population-level perspective is critical. Rational approaches to combining drugs with other forms of malaria control to reduce malaria transmission can only be made using transmission models informed by field data, given the difficulty of testing all combinations of interventions in all settings.

Cerebral malaria is a life-threatening complication of malaria caused by the parasite Plasmodium falciparum. The growing problem of drug resistance and the dearth of new antiparasitic drugs are a serious threat to the antimalaria treatment regimes. Studies on humans and the murine model have implicated the disruption of the blood–brain barrier (BBB) in the lethal course of the disease. Therefore, efforts to alleviate the BBB dysfunction could serve as an adjunct therapy. Here, we review the mechanisms associated with the disruption of the BBB. In addition, we discuss the current, still limited, knowledge on the contribution of different cell types, microparticles, and the kynurenine pathway in the regulation of BBB dysfunction, and how these molecules could be used as potential new therapeutic targets.

© 2016 Elsevier Ltd The failure of the Global Malaria Eradication Program (GMEP) during the 1960s highlighted the relevance of human movement to both re-introducing parasites in elimination settings and spreading drug-resistant parasites widely. Today, given the sophisticated surveillance of human movement patterns and key traveler groups, it is hoped that interventions can be implemented to protect and treat travelers, prevent onward transmission in low transmission settings, and eliminate sources of transmission, including sources of drug-resistant parasites.

Mutations in the Plasmodium falciparum genes Pfdhfr and Pfdhps have rendered sulfadoxine-pyrimethamine (SP) ineffective for malaria treatment in most regions of the world. Yet, SP is efficacious as intermittent preventive therapy in pregnant women (IPTp) and infants (IPTi) and as seasonal malaria control in children (SMC). SP-IPTp is being widely implemented in sub-Saharan Africa. SP-IPTi is recommended where the prevalence of SP-resistant malaria parasites is low, whereas SMC is recommended for areas of intense seasonal malaria transmission. The continuing success of these interventions depends largely on the prevalence of Pfdhfr and Pfdhps resistance mutations in the target population. Here we review the relationship between resistance mutations and SP-IPT within target populations in the context of monitoring and informing implementation of this intervention.

The definition of artemisinin resistance is becoming one of a prolonged parasite clearance phenotype, although this variable is a complex function of both host and parasite characteristics. We discuss some of the limitations of this definition of artemisinin resistance, particularly because of its potential global impact. This opinion article reviews the mechanisms underlying parasite clearance after artemisinin treatment and how these might relate to in vitro methods to assay for resistance. It revisits criteria for defining artemisinin resistance that are not currently being applied and suggests the term ‘treatment failure of artemisinin combination therapy' (TFACT) as a more accurate description of most cases of ‘artemisinin resistance'.

Plasmodium falciparum resistance to chloroquine, the former gold standard antimalarial drug, is mediated primarily by mutant forms of the ‘Chloroquine Resistance Transporter’ (PfCRT). These mutations impart upon PfCRT the ability to efflux chloroquine from the intracellular digestive vacuole, the site of drug action. Recent studies reveal that PfCRT variants can also affect parasite fitness, protect immature gametocytes against chloroquine action, and alter P. falciparum susceptibility to current first-line therapies. These results highlight the need to be vigilant in screening for the appearance of novel pfcrt alleles that could contribute to new multi-drug resistance phenotypes.

Population genetic strategies that leverage association, selection, and linkage have identified drug-resistant loci. However, challenges and limitations persist in identifying drug-resistance loci in malaria. In this review we discuss the genetic basis of drug resistance and the use of genome-wide association studies, complemented by selection and linkage studies, to identify and understand mechanisms of drug resistance and response. We also discuss the implications of nongenetic mechanisms of drug resistance recently reported in the literature, and present models of the interplay between nongenetic and genetic processes that contribute to the emergence of drug resistance. Throughout, we examine artemisinin resistance as an example to emphasize challenges in identifying phenotypes suitable for population genetic studies as well as complications due to multiple-factor drug resistance.

The worldwide use of artemisinin-based combination therapies (ACTs) has contributed in recent years to a substantial reduction in deaths resulting from Plasmodium falciparum malaria. Resistance to artemisinins, however, has emerged in Southeast Asia. Clinically, resistance is defined as a slower rate of parasite clearance in patients treated with an artemisinin derivative or an ACT. These slow clearance rates associate with enhanced survival rates of ring-stage parasites briefly exposed in vitro to dihydroartemisinin. We describe recent progress made in defining the molecular basis of artemisinin resistance, which has identified a primary role for the P. falciparum K13 protein. Using K13 mutations as molecular markers, epidemiological studies are now tracking the emergence and spread of artemisinin resistance. Mechanistic studies suggest potential ways to overcome resistance.

Although resistance to chloroquine (CQ) has relegated it from modern chemotherapeutic strategies to treat . Plasmodium falciparum malaria, new evidence suggests that higher doses of the drug may exert a different killing mechanism and offers this drug a new lease of life. Whereas the established antimalarial mechanisms of CQ are usually associated with nanomolar levels of the drug, micromolar levels of CQ trigger a distinct cell death pathway involving the permeabilization of the digestive vacuole of the parasite and a release of hydrolytic enzymes. In this paper, we propose that this pathway is a promising antimalarial strategy and suggest that revising the CQ treatment regimen may elevate blood drug levels to trigger this pathway without increasing the incidence of adverse reactions. © 2012 Elsevier Ltd.

In this review we present recent developments in the analysis of Plasmodium vivax clinical trials and ex vivo drug-susceptibility assays, as well approaches currently being used to identify molecular markers of drug resistance. Clinical trials incorporating the measurement of in vivo drug concentrations and parasite clearance times are needed to detect early signs of resistance. Analysis of P. vivax growth dynamics ex vivo have defined the criteria for acceptable assay thresholds for drug susceptibility testing, and their subsequent interpretation. Genotyping and next-generation sequencing studies in P. vivax field isolates are set to transform our understanding of the molecular mechanisms of drug resistance. © 2012 Elsevier Ltd.

With the advent of artemisinin resistance, it is timely to revisit the biological basis for the controversial suggestion that this class of antimalarial exerts its activity by inhibiting a calcium ATPase (PfATP6) that is most similar to sarcoplasmic endoplasmic reticulum calcium ATPases (SERCAs). Herein, evidence is discussed that relates to this hypothesis as alternative suggestions for how artemisinins might act have been reviewed elsewhere.

Current information on efficacy of antimalarials is crucial to provide early warning of resistance. A collaborative effort between the Global Malaria Program of the World Health Organization (WHO) and the WorldWide Antimalarial Resistance Network (WWARN) has recently been launched. The effort is planned as a collaboration with the scientific malaria community to create a global, comprehensive, and inclusive network that will provide quality-assured information on antimalarial drug resistance. © 2010 World Health Organization.

The evolution of resistance in Plasmodium falciparum against safe and affordable drugs such as chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) is a major global health threat. Investigating the dynamics of resistance against these antimalarial drugs will lead to approaches for addressing the problem of resistance in malarial parasites that are solidly based in evolutionary genetics and population biology. In this article, we discuss current developments in population biology modeling and evolutionary genetics. Despite great advancements achieved in the past decade, understanding the complex dynamics of mutations conferring drug resistance in P. falciparum requires approaches that consider the parasite population structure among other demographic processes.

This review summarizes recent investigations into antimalarial drug resistance and chemotherapy, including reports of some of the many exciting talks and posters on this topic that were presented at the third Molecular Approaches to Malaria meeting held in Lorne, Australia, in February 2008 (MAM 2008). After surveying this area of research, we focus on two important questions: what is the molecular contribution of pfcrt to chloroquine resistance, and what is the mechanism of action of artemisinin? We conclude with thoughts about the current state of antimalarial chemotherapy and priorities moving forward.

Four Plasmodium species cause malaria in humans: Plasmodium vivax is the most widespread and results in pronounced morbidity. India (population >1 billion) is a major contributor to the burden of vivax malaria. With a resurgence in interest concerning the neglected burden of vivax malaria and the completion of the P. vivax genome, it is timely to review what is known concerning P. vivax in India. The P. vivax population is highly diverse in terms of relapse patterns, drug response and clinical profiles, and highly genetically variable according to studies of antigen genes, isoenzyme markers and microsatellites. The unique epidemiology of malaria in India, where P. vivax predominates over Plasmodium falciparum, renders this location ideal for studying the dynamics of co-infection.

The contribution of underdosing to antimalarial treatment failure has been underappreciated. Most recommended dosage regimens are based on studies in non-pregnant adult patients. Young children and pregnant women, who bear the heaviest malaria burden, have the highest treatment failure rates. This has been attributed previously to lower immunity, although blood concentrations of many antimalarial drugs are significantly lower in pregnant women and young children than in non-pregnant adults. Nevertheless, there have been no studies of higher dosages. Sub-therapeutic concentrations will certainly contribute to poorer responses to treatment and will fuel the emergence and spread of antimalarial drug resistance. There is an urgent need for studies to optimise antimalarial dosage regimens in infants, young children and pregnant women, both to improve cure rates and to prolong the useful therapeutic lives of antimalarial drugs.

The spread of resistance of malaria infections to artemisinin is a major concern for the future. The Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K) may be a potential target of artemisinin and effector of resistance. This could be mediated by the Kelch13 protein, the molecular marker of resistance that modulates PfPI3K ubiquitination.

The evolution of antimalarial drug resistance is often considered to be a single-stage process in which parasites are either fully resistant or completely sensitive to a drug. However, this does not take into account the important intermediate stage of drug tolerance. Drug-tolerant parasites are killed by the high serum concentrations of drugs that occur during direct treatment of the human host. However, these parasites can spread in the human population because many drugs persist long after treatment, and the tolerant parasites can infect people in which there are residual levels of the drugs. This intermediate stage between fully sensitive and fully resistant parasites has far-reaching implications for the evolution of drug-resistant malaria.

Drug-resistant Plasmodium falciparum is a challenge to malaria control programs. Policy makers currently depend on in vivo (and, sometimes, in vitro ) resistance testing to set treatment guidelines. Molecular markers such as mutations in dhfr , dhps , pfcrt and pfmdr1 represent potential surveillance tools. In this article, we describe newer high-throughput methods for detecting these molecular markers. One method, 5′ nuclease real-time polymerase chain reaction, is discussed in detail.

Resistance of Plasmodium falciparum to the antimalarial drug sulfadoxine-pyrimethamine is a result of extremely rare mutations that have spread over large geographical areas. This pattern was completely unexpected because mutations encoding resistance occur commonly in laboratory conditions, leading to the expectation that resistance would originate locally on numerous occasions. This can be reconciled with basic P. falciparum biology and epidemiology, and it is concluded that this pattern of extremely rare mutations and subsequent spread should be regarded as the most likely pattern of resistance to future antimalarials. Consequently, strategies to slow the spread of resistance need to be designed on regional, rather than national, considerations.

Tropical countries increasingly face the burden of drug resistance in Plasmodium falciparum infections. Malaria-related mortality of African children rises in contrast to the decline of the overall mortality of children under five years of age in sub-Saharan Africa within the past four decades. The disaster can largely be attributed to antimalarial drug resistance in most malaria-endemic countries. The principles and mechanisms of chemoresistance in Plasmodium falciparum infections, in addition to the development and evaluation of new drugs and drug combinations, are major concerns of current malaria research and control strategies.

The maintenance of acidic pH in the digestive vacuole of the malaria parasite is thought to be crucial to the digestion of host cell haemoglobin and the subsequent process of heme detoxification. It may also be important in the mode of action of chloroquine and in the mechanism of resistance to the drug. Obtaining a definitive measurement of digestive vacuole pH has been surprisingly difficult. Some of the techniques for the measurement of pH in acid vesicles are outlined here along with some key aspects that are specific to malaria parasites. The use of acridine orange and dextran-tagged dyes as probes for the measurement of digestive vacuole pH has proved problematic, yet some surprising findings have emerged from work with these compounds.

Malaria is still considered a deadly scourge in Africa, Asia, and South America despite improved vector control and curative treatments with new antimalarial combinations. The next challenge is to work towards disease eradication. To achieve this goal it is crucial to develop, validate, and integrate biological assays into test cascades that align with the key target product profiles. For anti-relapse, a parent molecule should kill hypnozoites or cause activation of Plasmodium vivax liver stages. For transmission blocking, dual equal-activity antimalarials killing both the asexual and the sexual parasite stages in human blood are favored. Finally, by assessing cross resistance and generating drug resistance in the laboratory, it is expected that new medicines with acceptable resistance profiles will be forthcoming.

It is well recognized that drug resistance is the most significant obstacle to gaining effective malaria control. Despite the enormous advances in the knowledge of the biochemistry and molecular biology of malaria parasites, only a few genes determining resistance to the commonly used drugs have been identified. The idea that rodent malaria parasites should be exploited more widely for such work, in view of the practical problems of studying this subject experimentally in human malaria, is presented.

Udgivelsesdato: 2008-Feb Recent studies suggest that chloroquine resistance is mediated by an energy-dependent saturable chloroquine efflux carrier. An alternative explanation is that resistance is mediated by a channel. In Guinea-Bissau high doses of chloroquine are effective, well-tolerated and commonly used. This suggests that chloroquine resistance can be overcome by higher doses. Research on the mechanism of chloroquine resistance is of utmost importance and should include the effect of higher doses.

It has been recently reported that the prevalence of mutations associated with chloroquine resistance declined during the dry season. Fitness costs of drug resistance were suggested to be responsible for reduced survival of mutant parasites and only parasites surviving chronic infections were transmitted at the onset of the rainy season. This implies that during seasonal transmission significant changes can occur in allele frequency over the course of months rather than years. The practical consequences of these findings for monitoring dynamics of drug resistance markers are: (i) in areas of seasonal transmission the sampling date matters; (ii) fluctuations in mutation frequencies might be explained by seasonality; and (iii) a much awaited experimental determination of fitness costs of drug resistance becomes within reach.

Sulfadoxine-pyrimethamine (SP) is used throughout Africa for intermittent preventive treatment (IPT) of malaria, but resistance threatens its efficacy. We found marked regional differences in the genotypes responsible for SP resistance when mapping recent surveys of dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutations. In West Africa, a 'partially resistant' combination of dhfr N51I, N59R, and S108N with dhps A437G predominates, whereas in East Africa the 'fully resistant' combination of dhfr N51I, N59R, and S108N with dhps A437G+K540E is found. There are three East African foci where 'fully resistant' populations have additionally acquired dhps 581G and/or dhfr 164L to become 'super resistant'. SP-IPT in infants and pregnant women is reported to have failed in super resistant areas prompting review of SP-IPT use in affected areas.

Dondorp and Ringwald are concerned that malaria control efforts in the Greater Mekong Region may be compromised if questions are raised about the definition of artemisinin resistance [1]. Surely, it is the very best interpretation of available evidence that should underpin these efforts? That is what we have attempted to provide in our opinion article [2]. Our point that slower parasite clearance is not necessarily artemisinin resistance goes beyond semantics because of its implications for research and perhaps policy.

Until very recently, artemisinin and its derivatives were the only commercially available antimalarial drugs for which there was no reported parasite resistance. Artemisinin combination therapies (ACTs) are currently relied upon for effective malaria treatment in most regions of the world in which the disease is endemic, and their continuing efficacy is crucial if control and elimination programmes are to succeed. The loss of effectiveness of artemisinin and its derivatives to drug resistance would constitute a major disaster in the fight against malaria. To properly assess the danger posed by artemisinin resistance, and therefore enable appropriate and proportionate responses, definitions of ‘artemisinin resistance' and ‘ACT resistance', at both the clinical and parasitological levels, are needed.

Artemisinins are efficacious antimalarial drugs widely employed as first-line treatment in endemic countries under the form of combined therapies. Different molecular modes of action have been postulated to explain the parasiticidal effect of these compounds; however, none has been unequivocally accepted, and their physiological relevance is still questioned. Similarly, no definite genetic determinant of Plasmodium sensitivity to artemisinins has been identified so far. A better understanding of the mode of action of artemisinins and the genetic basis of laboratory-induced or field-observed altered susceptibility is crucial for malaria control. In this review different models of artemisinins' molecular action are briefly presented, focusing on recent advances, and the evidence of potential association between various gene polymorphisms and artemisinin resistance is comprehensively reviewed.

Huijben et al. [1] have recently made the provocative suggestion that sub-clearance drug treatment of clinical cases of Plasmodium falciparum malaria would prolong the effective life-span of the drug and should be preferred over the current treatment strategy that aims to eliminate all parasites as rapidly as possible. The article provides strong experimental data from a mouse model and is the latest in a growing literature with an evolutionary epidemiological framework that suggests that many of our current beliefs on the underlying causes of the spread of drug resistance and on resistance management are flawed or at best incomplete [2–5].

Antimalarial drug therapies containing artemisinins, 'ACTs', have become the mainstay for treating uncomplicated malaria in endemic countries. This is a major public health achievement requiring substantial political, financial and scientific input. The most compelling scientific argument for ACT deployment employed a very simple basic rationale that emphasised their role in slowing the origin of drug resistance while largely neglecting the additional role(s) of ACTs in slowing or preventing the spread of resistance once it has arisen. Recent reports suggest that early stages of resistance to artemisinins and/or its partner drugs could be occurring, thus it is timely to briefly review exactly how ACTs slow the origin and spread of resistance and to interpret the threat of resistance within this context.

Artemisinin combination therapy (ACT) paves the way for new opportunities to eliminate malaria in the tropics. However, the huge increase of ACT consumption raises major concerns about their availability over the next few years. At the same time a decrease in their efficacy has already been reported. Alongside the deployment of multifocal control programs, the process ranging from artemisia crop production to accreditation of new ACT combinations urgently needs to be strengthened to supply sufficient quantities of high-quality drugs. New suppliers will have the opportunity to enter this market to develop new formulations, and bioequivalence studies are required to validate these new formulations. It is thus crucial for national malaria control teams to be able to better scrutinize the dossier of these new formulations.

Chloroquine resistant malaria (CQR) emerged in East Africa during the late 1970s and then spread westward. A molecular marker only became available in the late 1990s, and by that time CQR had permeated throughout Africa. By contrast, resistance to sulphadoxine-pyrimethamine (SPR) has emerged during an era of molecular surveillance, and the changing prevalence of SPR conferred by point mutations in the dhfr and dhps genes has been recorded in hundreds of sites across Africa. We have collated and mapped reports of the dhps K540E mutation, a uniquely informative marker of SPR, and used these to describe the geography of its dispersal through time. Like CQR, dhps K540E appeared first in East Africa and spread west. We discuss whether there are common principles governing resistance dispersal in Africa and how these might guide surveillance in future.

Virulence and drug resistance are traits that pathogens can acquire independently, albeit these traits can influence each other. A recent publication has reported on the co-evolution of virulence and pyrimethamine resistance in malaria parasites. Here, we discuss this finding in the context of the folate biosynthesis pathway and explain how mutational changes in this pathway can affect both parasite replication rates and the development of drug resistance.