Costanzo Marna S, Hartl Daniel L
Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.
J Genet. 2011 Aug;90(2):187-90. doi: 10.1007/s12041-011-0072-z.
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.
恶性疟原虫对抗叶酸药物的耐药性已有充分描述，并且在临床环境中已观察到数十年。在分子水平上，已鉴定出导致耐药性的二氢叶酸还原酶（dhfr）基因突变，并且野生型和突变型二氢叶酸还原酶与天然底物和药物复合物的晶体结构已得到解析。然而，我们才刚刚开始理解导致该系统中耐药性进化的进化压力的复杂性。允许疟原虫蛋白异源表达的微生物系统为研究进化模式提供了一种易于处理的方法，这些模式可以为我们最终理解影响临床环境中耐药性进化的更复杂因素提供信息。在本文中，我们将回顾在大肠杆菌和酿酒酵母表达系统中的工作，这些工作探索了与耐药性相关的突变的适应性景观，并表明：（i）耐药性的进化途径数量有限，且出现概率很高；（ii）维持高水平耐药性所带来的适应性代价适中；（iii）不同的抗叶酸药物可能会施加相反的选择压力。
