In this Review, David Fidock discusses malarial resistance to artemisinin-based combination therapies, among others, and presents strategies for designing new therapeutics and to overcome resistance. The global adoption of artemisinin-based combination therapies (ACTs) in the early 2000s heralded a new era in effectively treating drug-resistant Plasmodium falciparum malaria. However, several Southeast Asian countries have now reported the emergence of parasites that have decreased susceptibility to artemisinin (ART) derivatives and ACT partner drugs, resulting in increasing rates of treatment failures. Here we review recent advances in understanding how antimalarials act and how resistance develops, and discuss new strategies for effectively combatting resistance, optimizing treatment and advancing the global campaign to eliminate malaria.

Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic.

Chloroquine, a previous highly efficacious, easy to use and affordable anti-malarial agent was withdrawn from malaria endemic regions due to high levels of resistance. This review collated evidence from published-reviewed articles to establish prevalence of Pfcrt 76T and Pfmdr-1 86Y alleles in malaria affected countries following official discontinuation of chloroquine use. A review protocol was developed, registered in PROSPERO (#CRD42018083957) and published in a peer-reviewed journal. Article search was done in PubMed, Scopus, Lilacs/Vhl and Embase databases by two experienced librarians (AK, RS) for the period 1990-to-Febuary 2018. Mesh terms and Boolean operators (AND, OR) were used. Data extraction form was designed in Excel spread sheet 2007. Data extraction was done by three reviewers (NL, BB and MO), discrepancies were resolved by discussion. Random effects analysis was done in Open Meta Analyst software. Heterogeneity was established using I2-statistic. A total of 4721 citations were retrieved from article search (Pubmed = 361, Lilac/vhl = 28, Science Direct = 944, Scopus = 3388). Additional targeted search resulted in three (03) eligible articles. After removal of duplicates (n = 523) and screening, 38 articles were included in the final review. Average genotyping success rate was 63.6% (18,343/28,820) for Pfcrt K76T and 93.5% (16,232/17,365) for Pfmdr-1 86Y mutations. Prevalence of Pfcrt 76T was as follows; East Africa 48.9% (2528/5242), Southern Africa 18.6% (373/2163), West Africa 58.3% (3321/6608), Asia 80.2% (1951/2436). Prevalence of Pfmdr-1 86Y was; East Africa 32.4% (1447/5722), Southern Africa 36.1% (544/1640), West Africa 52.2% (1986/4200), Asia 46.4% (1276/2217). Over half, 52.6% (20/38) of included studies reported continued unofficial chloroquine use following policy change. Studies done in Madagascar and Kenya reported re-emergence of chloroquine sensitive parasites (IC50   95%). The prevalence of chloroquine resistance alleles among Plasmodium falciparum parasites have steadily declined since discontinuation of chloroquine use. However, Pfcrt K76T and Pfmdr-1 N86Y mutations still persist at moderate frequencies in most malaria affected countries.

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Persistence of chloroquine resistance alleles in malaria endemic countries: a systematic review of burden and risk factors.

Plasmodium falciparum and Plasmodium vivax, the two protozoan parasite species that cause the majority of cases of human malaria, have developed resistance to nearly all known antimalarials. The ability of malaria parasites to develop resistance is primarily due to the high numbers of parasites in the infected person's bloodstream during the asexual blood stage of infection in conjunction with the mutability of their genomes. Identifying the genetic mutations that mediate antimalarial resistance has deepened our understanding of how the parasites evade our treatments and reveals molecular markers that can be used to track the emergence of resistance in clinical samples. In this review, we examine known genetic mutations that lead to resistance to the major classes of antimalarial medications: the 4-aminoquinolines (chloroquine, amodiaquine and piperaquine), antifolate drugs, aryl amino-alcohols (quinine, lumefantrine and mefloquine), artemisinin compounds, antibiotics (clindamycin and doxycycline) and a napthoquinone (atovaquone). We discuss how the evolution of antimalarial resistance informs strategies to design the next generation of antimalarial therapies.

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The genomic architecture of antimalarial drug resistance

Since 2000, the world has made significant progress in reducing malaria morbidity and mortality, and several countries in Africa, South America and South-East Asia are working hard to eliminate the disease. These elimination efforts continue to rely heavily on antimalarial drugs and insecticide-based interventions, which remain the cornerstones of malaria treatment and prevention. However, resistance has emerged against nearly every antimalarial drug and insecticide that is available. In this review we discuss the evolutionary consequences of the way we currently implement antimalarial interventions, which is leading to resistance and may ultimately lead to control failure, but also how evolutionary principles can be applied to extend the lifespan of current and novel interventions. A greater understanding of the general evolutionary principles that are at the core of emerging resistance is urgently needed if we are to develop improved resistance management strategies with the ultimate goal to achieve a malaria-free world.

http://diposit.ub.edu/dspace/bitstream/2445/121847/1/huijben2018_3010.pdf

Putting evolution in elimination: Winning our ongoing battle with evolving malaria mosquitoes and parasites.

Introduction: Plasmodium falciparum, the deadly agent of malaria, is notorious for its capacity to develop drug resistance. Treatment failures of artemisinin therapy regimens (ACTc), the present mainstay, is emerging. The transporter coding pfmdr1 gene is a central node in this process, having been associated with in vitro and in vivo parasite response to a broad range of ACT antimalarials.Areas covered: The review covers the historical origins of the pfmdr1 discovery, followed by a detailed description of its sequence and expression characteristics, as well as the structural and functional characteristics of its coded transmembrane protein. pfmdr1 association with ACT drugs response in vivo and in vitro is thoroughly reviewed. A reference is made to significant compounds presently in the development pipeline.The literature search was focused on Pubmed based searches with occasional resource to edited books, World Health Organization documentation and conference reports for adding valuable details...

pfmdr1 (Plasmodium falciparum multidrug drug resistance gene 1): a pivotal factor in malaria resistance to artemisinin combination therapies

Molecular surveillance of Plasmodium falciparum drug resistance markers reveals partial recovery of chloroquine susceptibility but sustained sulfadoxine-pyrimethamine resistance at two sites of different malaria transmission intensities in Rwanda.

Steven Tukwasibwe

Papers

Molecular surveillance of Plasmodium falciparum drug resistance markers reveals partial recovery of chloroquine susceptibility but sustained sulfadoxine-pyrimethamine resistance at two sites of different malaria transmission intensities in Rwanda.