The evolutionary landscape of antifolate resistance in Plasmodium falciparum.
The evolutionary landscape of antifolate resistance in Plasmodium falciparum.
复制标题
恶性疟原虫抗卵形抗性的进化景观。
DOI：
10.1007/s12041-011-0072-z
复制
发表时间：
2011-08
影响因子：
1.5
通讯作者：
Hartl DL
中科院分区：
文献类型：
--
作者：
Costanzo MS;Hartl DL
Resistance to antifolates in Plasmodium falciparum is well described and has been observed in clinical settings for decades. At the molecular level, point mutations in the dhfr gene that lead to resistance have been identified, and the crystal structure of the wildtype and mutant dihydrofolate reductase enzymes have been solved in complex with native substrate and drugs. However, we are only beginning to understand the complexities of the evolutionary pressures that lead to the evolution of drug resistance in this system. Microbial systems that allow heterologous expression of malarial proteins provide a tractable way to investigate patterns of evolution that can inform our eventual understanding of the more complex factors that influence the evolution of drug resistance in clinical settings. In this paper we will review work in Escherichia coli and Saccharomyces cerevisiae expression systems that explore the fitness landscape of mutations implicated in drug resistance and show that (i) a limited number of evolutionary pathways to resistance are followed with high probability; (ii) fitness costs associated with the maintenance of high levels of resistance are modest; and (iii) different antifolates may exert opposing selective forces.
