ReviewSpread and evolution of Plasmodium falciparum drug resistance
Introduction
Since the 1940s, the development of antimalarials has been playing a great role in controlling malaria. However, worldwide use of antimalarials has produced tremendous selective pressure on Plasmodium falciparum and caused the spread of resistant parasites with increased malaria morbidity and mortality. To date, resistance to all the commonly used antimalarials, except for the recently used artemisinin and its derivatives, has been reported. In particular, reduced efficacy of two conventional antimalarials drugs, chloroquine (CQ) and sulfadoxine/pyrimethamine (SP), for the treatment of uncomplicated falciparum malaria is a serious concern in many endemic areas.
After the discovery of genes that are involved in the parasite's resistance to CQ and SP, the molecular mechanisms of the action of these conventional antimalarials are becoming unveiled [1], [2]. At the same time, molecular population genetic analyses using sophisticated methods to determine the patterns of microsatellite variability flanking the resistance genes have elucidated the geographic origins and spread of parasite drug resistance. Until recently, it was widely believed that drug resistance is frequently generated in endemic areas. However, molecular population genetic analyses using microsatellite markers have shown that the origins of resistant lineages of both CQ and SP are considerably limited, and that restricted resistant lineages spread to wide geographic areas [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]. Here, we review recent studies of the emergence, prevalence, and geographical spread of CQ and SP resistant lineages, revealed by molecular population genetic analysis of P. falciparum populations. Recent progress in understanding the mechanisms for the parasite's resistance to these drugs is outlined briefly. For those who are interested in molecular details of the mechanism, see reviews by others [2], [14], [15].
Section snippets
CQ resistance
CQ acts as a schizontocide by preventing the development of blood-stage malaria parasites. Although the schizontocidal mechanism of CQ has not been fully elucidated, it is believed that CQ acts by binding to heme molecules in the parasite food vacuole, which is a by-product of parasite's digesting step from hemoglobin. Heme is a toxic intermediate that is detoxified by polymerization into an inert microcrystalline called hemozoin, which is recognized as ‘malaria pigment’ by light microscopy. CQ
SP resistance
Antifolate effects of SP are derived from the inhibition of two enzymes in the folate synthesis pathway, dihydrofolate reductase (DHFR) [49] by pyrimethamine and dihydropteroate synthase (DHPS) [50], [51] by sulfadoxine. P. falciparum undergoes de novo synthesis of folate from precursors GTP, p-aminobenzoic acid (pABA), and l-glutamine. Pyrimethamine binds far more strongly to the parasite DHFR than to the mammalian enzyme. Inhibition of DHFR and DHPS in the parasite folate synthesis pathway
Origins and spread of CQ resistance
In pfcrt, mutations resulting in amino acid changes at positions 72–76 are strongly associated with geographic region-restricted evolution of P. falciparum resistance to CQ. Other polymorphisms outside these positions, however, have no clear geographical association, and thus the evolution and geographical spread of resistance can be estimated by the genotyping of pfcrt at positions 72–76 and microsatellite haplotyping flanking this locus.
Origins and spread of SP resistance
The first field trial of pyrimethamine monotherapy for the treatment of P. falciparum was carried out in African children in 1951 [109]. At that time CQ was effective and thus pyrimethamine was mainly used for mass drug administration or prophylaxis of malaria. However, resistance to pyrimethamine appeared during or shortly after trials of mass eradication or prophylaxis in many endemic regions [110], [111], [112], [113]. SP was initially used in Thailand in the late 1960s as a first-line
Concluding remarks
Recent progress in molecular population genetic studies of P. falciparum drug resistance has greatly promoted our understanding of the emergence, prevalence, and geographical spread of drug resistant lineages. In many endemic regions, the spread of parasites resistant to either CQ or SP appears to have resulted from the migration of limited resistant lineages. It is of interest to see that the number of resistant lineages is restricted not only in CQ but also in SP, although mechanisms for
Acknowledgements
This study was supported by the Takeda Science Foundation, a Grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (18GS03140013, 17590380, 18073013, 20390120) and a Grant-in-aid from the Ministry of Health, Labour and Welfare of Japan (H20-Shinkou-ippan-013).
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