fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in plasmodium falciparum健身权衡二氢叶酸还原酶的进化和恶性疟原虫的耐药性.pdfVIP

Fitness Trade-Offs in the Evolution of Dihydrofolate Reductase and Drug Resistance in Plasmodium falciparum Marna S. Costanzo*, Kyle M. Brown, Daniel L. Hartl Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, United States of America Abstract Background: Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the folate pathway. However, a handful of mutations in the gene coding for one such enzyme, dihydrofolate reductase, confer drug resistance. Understanding how evolution proceeds from drug susceptibility to drug resistance is critical if new antifolate treatments are to have sustained usefulness. Methodology/Principal Findings: We use a transgenic yeast expression system to build on previous studies that described the adaptive landscape for the antifolate drug pyrimethamine, and we describe the most likely evolutionary trajectories for the evolution of drug resistance to the antifolate chlorcycloguanil. We find that the adaptive landscape for chlorcycloguanil is multi-peaked, not all highly resistant alleles are equally accessible by evolution, and there are both commonalities and differences in adaptive landscapes for chlorcycloguanil and pyrimethamine. Conclusions/Significance: Our findings suggest that cross-resistance between drugs targeting the same enzyme reflect the fitness landscapes associated with each particular drug and the position of the genotype on both landscapes. The possible public health implications of these findings are discussed. Citation: Costanzo MS, Brown KM, Hartl DL (2011) Fitness Trade-Offs in the Evolution of Dihydrofolate Reductase