Impaired fitness of drug-resistant malaria parasites: evidence and implication on drug-deployment policies

被引:34
作者
Babiker, Hamza A. [1 ,2 ]
Hastings, Ian M. [3 ]
Swedberg, Gote [4 ]
机构
[1] Univ Edinburgh, Sch Biol Sci, Edinburgh EH9 3JT, Midlothian, Scotland
[2] Sultan Qaboos Univ, Fac Med, Dept Biochem, Muscat, Oman
[3] Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England
[4] Uppsala Univ, Biomed Ctr, Dept Med Biochem & Microbiol, SE-75123 Uppsala, Sweden
关键词
chloroquine; drug-resistant genotype; fitness cost; Plasmodium chabaudi; Plasmodium falciparum; pyrimethamine; sulfadoxine; FALCIPARUM DIHYDROFOLATE-REDUCTASE; SULFADOXINE-PYRIMETHAMINE RESISTANCE; PLASMODIUM-FALCIPARUM; CHLOROQUINE RESISTANCE; DIHYDROPTEROATE SYNTHETASE; ANTIMALARIAL RESISTANCE; POPULATION-STRUCTURE; COMPETITIVE RELEASE; MUTATIONS; TRANSMISSION;
D O I
10.1586/ERI.09.29
中图分类号
R51 [传染病];
学科分类号
100201 [内科学];
摘要
Malaria, a leading parasitic disease, inflicts an enormous toll on human lives and is caused by protozoal parasites belonging to the genus Plasmodium. Antimalarial drugs targeting essential biochemical processes in the parasite are the primary resources for management and control. However, the parasite has established mutations, substantially reducing the efficacy of these drugs. First-line therapy is faced the with the consistent evolution of drug-resistant genotypes carrying these mutations. However, drug-resistant genotypes are likely to be less fit than the wild-type, suggesting that they might disappear by reducing the volume of drug pressure. A substantial body of epidemiological evidence confirmed that the frequency of resistant genotypes wanes when active drug selection declines. Drug selection on the parasite genome that removes genetic variation in the vicinity of drug-resistant genes (hitch-hiking) is common among resistant parasites in the field. This can further disadvantage drug-resistant strains and limit their variability in the face of a mounting immune response. Attempts to provide unequivocal evidence for the fitness cost of drug resistance have monitored the outcomes of laboratory competition experiments of deliberate mixtures of sensitive and resistant strains, in the absence of drug pressure, using isogenic clones produced either by drug selection or gene manipulation. Some of these experiments provided inconclusive results, but they all suggested reduced fitness of drug-resistant clones in the absence of drug pressure. In addition, biochemical analyses provided clearer information demonstrating that the mutation of some anti malarial-targeted enzymes lowers their activity compared with the wild-type enzyme. Here, we review current evidences for the disadvantage of drug-resistance mutations, and discuss some strategies of drug deployment to maximize the cost of resistance and limit its spread.
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页码:581 / 593
页数:13
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