Question

3) What is the relationship between gch1 copy number and downstream genes in the folate biosynthesis pathway that already confer drug resistance to the parasite?

Answer 1

In the centuries past, the main weapon against human malaria infections continues to be intervention with drugs inspite of the the widespread and increasing frequency of parasite populations that are resistant to one or more of the available compounds. This is a particular problem with the lethal species of parasite, Plasmodium falciparum, causing enormous social and economic problems. A series of four nonsynonymous amino acid substitutions at the targeted enzyme, dihydrofolate reductase (DHFR), render the parasites highly resistant to the antifolate drug pyrimethamine. The stepwise gain of these four dhfr mutations results in tradeoffs between pyrimethamine resistance and parasite fitness. The epistatic interaction between dhfr mutations and amplification of the gene encodes the first upstream enzyme in the folate pathway, GTP cyclohydrolase I (GCH1). gch1 amplification confers low level pyrimethamine resistance and thus be selected for pyrimethamine treatment. The gch1 amplification can then be co-opted by the parasites because it reduces the cost of acquiring drug-resistant dhfr mutations downstream in the same metabolic pathway. The evolution of robustness during the gain of drug-resistant mutations has broad implications for both the development of new drugs and molecular surveillance for resistance to existing drugs.