Controlling the spread of antimalarial drug resistance, especially resistance of Plasmodium falciparum to artemisinin-based combination therapies, is a high priority. Available data indicate that, as with other microorganisms, the spread of drug-resistant malaria parasites is limited by fitness costs that frequently accompany resistance. Resistance-mediating polymorphisms in malaria parasites have been identified in putative drug transporters and in target enzymes. The impacts of these polymorphisms on parasite fitness have been characterized in vitro and in animal models. Additional insights have come from analyses of samples from clinical studies, both evaluating parasites under different selective pressures and determining the clinical consequences of infection with different parasites. With some exceptions, resistance-mediating polymorphisms lead to malaria parasites that, compared with wild type, grow less well in culture and in animals, and are replaced by wild type when drug pressure diminishes in the clinical setting. In some cases, the fitness costs of resistance may be offset by compensatory mutations that increase virulence or changes that enhance malaria transmission. However, not enough is known about effects of resistance mediators on parasite fitness. A better appreciation of the costs of fitness-mediating mutations will facilitate the development of optimal guidelines for the treatment and prevention of malaria.

译文

控制抗疟药耐药性的传播,特别是恶性疟原虫对青蒿素类联合疗法的耐药性,是当务之急。现有数据表明,与其他微生物一样,抗药性疟疾寄生虫的传播受到经常伴随抗药性的健身成本的限制。已在假定的药物转运蛋白和靶酶中发现了疟疾寄生虫的抗性介导多态性。这些多态性对寄生虫适应性的影响已在体外和动物模型中得到表征。来自临床研究样本的分析还提供了其他见解,既评估了不同选择压力下的寄生虫,又确定了感染不同寄生虫的临床后果。除某些例外,抗性介导的多态性导致疟疾寄生虫,与野生型相比,其在培养物和动物中的生长较差,并且在临床环境中药物压力降低时被野生型取代。在某些情况下,抗药性的适应性成本可能会被增加毒力的补偿性突变或增强疟疾传播的变化所抵消。然而,对抗性介质对寄生虫适应性的影响知之甚少。更好地了解健康中介突变的成本将有助于制定治疗和预防疟疾的最佳指南。

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